Succinoylamino lactams as inhibitors of a-β protein production

ABSTRACT

This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer&#39;s disease and Down&#39;s Syndrome.

RELATED CROSS-REFERENCES

This application is a divisional of U.S. patent application Ser. No. 11/492,593, filed Jul. 25, 2006, which is a continuation of U.S. patent application Ser. No. 11/175,644, filed Jul. 6, 2005, which is a divisional of U.S. patent application Ser. No. 10/285,776, filed Nov. 1, 2002, which is a divisional of U.S. patent application Ser. No. 09/506,360, filed Feb. 17, 2000, now U.S. Pat. No. 6,794,381, issued Sep. 21, 2004, which is a continuation-in-part of U.S. patent application Ser. No. 09/370,089, filed Aug. 6, 1999, now abandoned, Provisional Application Ser. No. 60/095,698, filed Aug. 7, 1998, and Provisional U.S. Patent Application Ser. No. 60/120,227, filed Feb. 15, 1999, and Provisional Application Ser. No. 60/113,558, filed Dec. 23, 1998; the disclosures of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer's disease and Down's Syndrome.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotional stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol. 1994, 10: 373-403).

Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down's Syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).

Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated Aβ, β-amyloid peptide, and sometimes β/A4; referred to herein as Aβ. In addition to deposition of Aβ in amyloid plaques, Aβ is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Aβ was first purified, and a partial amino acid reported, in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.

Compelling evidence accumulated during the last decade revealed that Aβ is an internal polypeptide derived from a type 1 integral membrane protein, termed β amyloid precursor protein (APP). β APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Aβ is derived from cleavage of β APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.

The existence of at least four proteolytic activities has been postulated. They include β secretase(s), generating the N-terminus of Aβ, a secretase(s) cleaving around the 16/17 peptide bond in Aβ, and γ secretases, generating C-terminal Aβ fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.

Several lines of evidence suggest that abnormal accumulation of Aβ plays a key role in the pathogenesis of AD. Firstly, Aβ is the major protein found in amyloid plaques. Secondly, Aβ is neurotoxic and may be causally related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of β APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other β APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human b APP. Fifthly, individuals with Down's syndrome have an increased gene dosage of β APP and develop early-onset AD. Taken together, these observations strongly suggest that Aβ depositions may be causally related to the AD.

It is hypothesized that inhibiting the production of Aβ will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Aβ production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Aβ in vivo.

Methods of treatment could target the formation of Aβ through the enzymes involved in the proteolytic processing of b amyloid precursor protein. Compounds that inhibit b or g secretase activity, either directly or indirectly, could control the production of Aβ. Advantageously, compounds that specifically target g secretases, could control the production of Aβ. Such inhibition of β or γ secretases could thereby reduce production of Aβ, which, thereby, could reduce or prevent the neurological disorders associated with Aβ protein.

PCT publication number WO 96/29313 discloses the general formula:

covering metalloprotease inhibiting compounds useful for the treatment of diseases associated with excess and/or unwanted matrix metalloprotease activity, particularly collagenase and or stromelysin activity.

Compounds of general formula:

are disclosed in PCT publication number WO 95/22966 relating to matrix metalloprotease inhibitors. The compounds of the invention are useful for the treatment of conditions associated with the destruction of cartilage, including corneal ulceration, osteoporosis, periodontitis and cancer.

European Patent Application number EP 0652009A1 relates to the general formula:

and discloses compounds that are protease inhibitors that inhibit Aβ production.

U.S. Pat. No. 5,703,129 discloses the general formula:

which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives that inhibit Aβ production and are useful in the treatment of Alzheimer's disease.

None of the above references teaches or suggests the compounds of the present invention which are described in detail below.

SUMMARY OF THE INVENTION

One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Aβ protein or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of Formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, wherein R³, R^(3a), R⁵, R^(5a), R⁶, A, Q, B, W, X, Y, and Z are defined below, are effective inhibitors of the production of Aβ.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Thus, in a first embodiment, the present invention provides a novel compound of Formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   A is O or S; -   Q is —OR¹ or —NR¹R²; -   R¹, at each occurrence, is independently selected from:     -   H;     -   C₁-C₆ alkyl substituted with 0-3 R^(1a);     -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);     -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and     -   5 to 10 membered heterocycle substituted with 0-3 R^(1b); -   R^(1a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);     -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and     -   5 to 6 membered heterocycle substituted with 0-3 R^(1b); -   R^(1b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R² is independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆     alkoxy, phenoxy, benzyloxy, C₃-C₁₀ carbocycle, C₆-C₁₀ aryl and 5 to     10 membered heterocycle; -   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R⁷)_(n)—N(R^(7b))C(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C(═O)N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—N(R^(7b))S(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—S(═O)₂N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, 2, or 3; -   m is 0, 1, 2, or 3; -   R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄ alkenyloxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₆ alkyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkenyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkynyl substituted with 0-3 R^(4a),     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, Br, I, CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄     haloalkoxy, and C₁-C₄ halothioalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄     haloalkoxy, and C₁-C₄ halothioalkoxy; -   R⁶ is H;     -   C₁-C₆ alkyl substituted with 0-3 R^(6a);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(6b); or     -   C₆-C₁₀ aryl substituted with 0-3 R^(6b); -   R^(6a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CF₃; -   R^(6b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, aryl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H and C₁-C₄ alkyl; -   W is —(CR⁸R^(8a))_(p)—; -   p is 0, 1, 2, 3, or 4; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄     haloalkoxy, and C₁-C₄ halothioalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, 2, or 3; -   u is 0, 1, 2, or 3; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,     —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or     —OC(═O)—; -   Z is C₁-C₄ alkyl substituted with 0-3 R^(12b);     -   C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄     haloalkoxy, and C₁-C₄ halothioalkoxy; -   B is a 5 to 10 membered lactam or thiolactam,     -   wherein the lactam or thiolactam is saturated, partially         saturated or unsaturated;     -   wherein each additional lactam carbon or thiolactam carbon is         substituted with 0-2 R¹¹; and,     -   optionally, the lactam or thiolactam contains a heteroatom         selected from —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)R¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)NR¹⁸R¹⁹, S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-2 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,     acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄     haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,         C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄     haloalkoxy, and C₁-C₄ halothioalkoxy; -   R¹⁴, at each occurrence, is independently selected from H, phenyl,     benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, aryl-CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

In a preferred embodiment the present provides

-   A is O; -   Q is —NR¹R²; -   R¹, at each occurrence, is independently selected from:     -   H;     -   C₁-C₆ alkyl substituted with 0-3 R^(1a);     -   C₂-C₆ alkenyl substituted with 0-3 R^(1a); -   R^(1a), at each occurrence, is independently selected from H, OR¹⁴,     F, ═O, NR¹⁵R¹⁶, CF₃;     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(1b);     -   phenyl substituted with 0-3 R^(1b); and     -   5 to 6 membered heterocycle substituted with 0-3 R^(1b); -   R^(1b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R² is independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆     alkoxy, phenoxy, and benzyloxy; -   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—NHC(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C(═O)NH—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—NHS(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—S(═O)₂NH—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, 2, or 3; -   m is 0, 1, 2, or 3; -   R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄ alkenyloxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₆ alkyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkenyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkynyl substituted with 0-3 R^(4a),     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, Br, I, CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁶ is H;     -   C₁-C₆ alkyl substituted with 0-3 R^(6a);     -   C₃-C₆ carbocycle substituted with 0-3 R^(6b); or     -   C₆-C₁₀ aryl substituted with 0-3 R^(6b); -   R^(6a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CF₃; -   R^(6b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, aryl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H and C₁-C₄ alkyl; -   W is —(CR⁸R^(8a))_(p)—; -   p is 0, 1, 2, 3, or 4; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, 2, or 3; -   u is 0, 1, 2, or 3; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,     —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or     —OC(═O)—; -   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   B is a 6, 7, or 8 membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-1 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,         C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

In a further preferred embodiment the present invention provides

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, or 2; -   m is 0, 1, or 2; -   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, or butoxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, Br, I CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);     -   R^(4b), at each occurrence, is independently selected from H,         OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,         S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄         haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁶ is H, methyl, or ethyl; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, phenyl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H, methyl, ethyl, propyl, and     butyl; -   W is —(CR⁸R^(8a))_(p)—; -   p is 0, 1, or 2; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl and C₃-C₆     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-2 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, or 2; -   u is 0, 1, or 2; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl or C₃-C₆ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     —C(═O)NR^(19b), —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—,     —NR^(19b)S(═O)—, or —S(═O)NR^(19b)—; -   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   B is a seven membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-1 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,         C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸ at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

In a further preferred embodiment the present invention provides

-   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0 or 1; -   m is 0 or 1; -   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, or butoxy; -   R⁴ is H, OH,     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-1 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, butoxy, or allyl; -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   R⁶ is H; -   R⁷, at each occurrence, is independently selected from H, F, CF₃,     methyl, and ethyl; -   R^(7a), at each occurrence, is independently selected from H, F,     CF₃, methyl, and ethyl; -   R^(7b) is independently selected from H, methyl, and ethyl; -   W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   B is a seven membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;     -   C₁-C₄ alkyl substituted with 0-1 R^(10a);     -   phenyl substituted with 0-4 R^(10b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or     -   5 to 6 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, CF₃;     -   C₁-C₄ alkyl substituted with 0-1 R^(11a);     -   phenyl substituted with 0-3 R^(11b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3     R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,     4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,     (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,     propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or     ethoxyethyl; -   R¹⁸, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and -   R¹⁹, at each occurrence, is independently selected from H, methyl,     and ethyl.

In a more preferred embodiment the present invention provides

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R³ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂(CH₃)₂,     —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃,     —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂,     —CH₂CH═C(CH₃)₂, —CH₂CH₂CH═CH₂, —CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂,     cis-CH₂CH═CH(CH₃), cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),     trans-CH₂CH₂CH═CH(CH₃); —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃),     cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,     cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,     cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—, phenyl-CH₂—,     (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,     (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,     (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,     (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,     (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,     (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,     (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl—F-phenyl)CH₂—,     phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,     (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—,     (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—,     (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—,     (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—,     (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,     (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,     (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,     (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,     (3-F-5-Cl-phenyl)CH₂CH₂—, or -   R⁵ is —CH₃, —CH₂CH₃, —CH-2CH₂CH₃, —CH₂(CH₃)₂, —CH₂CH₂CH₂CH₃,     —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃,     —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH(CH₂CH₃)₂,     —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH═CH₂,     —CH₂CH═CH₂, —CH═CHCH₃, cis-CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),     trans-CH₂CH═CH(C₆H₅), —CH₂CH═C(CH₃)₂, cis-CH₂CH═CHCH₂CH₃,     trans-CH₂CH═CHCH₂CH₃, cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃),     trans-CH₂CH═CHCH₂(C₆H₅), —C≡CH, —CH₂CO—CH, —CH₂C≡C(CH₃),     —CH₂C≡C(C₆H₅) —CH₂CH₂C≡CH, —CH₂CH₂C≡C(CH₃), —CH₂CH₂C≡C(C₆H₅)     —CH₂CH₂CH₂C≡CH, —CH₂CH₂CH₂C≡C(CH₃), —CH₂CH₂CH₂O—C(C₆H₅)     cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,     cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—, (3-CH₃-cyclobutyl)CH₂—,     cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—,     cyclohexyl-CH₂CH₂—, (2-CH₃-cyclopropyl)CH₂CH₂—,     (3-CH₃-cyclobutyl)CH₂CH₂—, phenyl-CH₂—, (2-F-phenyl)CH₂—,     (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, furanyl-CH₂—, thienyl-CH₂—,     pyridyl-CH₂—, 1-imidazolyl-CH₂—, oxazolyl-CH₂—, isoxazolyl-CH₂—,     phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,     (4-F-phenyl)CH₂CH₂—, furanyl-CH₂CH₂—, thienyl-CH₂CH₂—,     pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—,     isoxazolyl-CH₂CH₂—, -   W is a bond, —CH₂—, or —CH(CH₃)—; -   Y is a bond;

-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or     —N(CH₃)—, -   Z is phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl,     3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl,     2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl,     2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl,     3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl,     3-Cl—F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl,     2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl,     4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl,     thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl,     1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl,     cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl,     phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,     (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,     (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,     (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,     (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,     (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,     (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl—F-phenyl)CH₂—,     (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—,     (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—,     (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—,     (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—,     (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—,     (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—,     (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—,     (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—,     (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-piperidinyl)CH₂—,     phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—,     (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,     (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—,     (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—,     (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—,     (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,     (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,     (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,     (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,     (3-F-5-Cl-phenyl)CH₂CH₂—, (3-Cl—F-phenyl)CH₂CH₂—,     (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—,     (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—, (4-Me-phenyl)CH₂CH₂—,     (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—,     (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,     (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—,     (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,     (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,     (isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—, (cyclopropyl)CH₂CH₂—,     (cyclobutyl)CH₂CH₂—, (cyclopentyl)CH₂CH₂—, (cyclohexyl)CH₂CH₂—,     (morpholino)CH₂CH₂—, (N-piperidinyl)CH₂CH₂—, -   B is a seven membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,     (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,     (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,     (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,     (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—; -   R¹¹, at each occurrence, is independently selected from H, ═O,     methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,     (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,     (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,     (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,     (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—; and -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical.

In a further more preferred embodiment the present invention provides

-   B is

In an even more preferred embodiment the present invention provides

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R³ is R⁴, -   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a), -   R^(4a), at each occurrence, is independently selected from is     -   H, F, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   W is —CH₂—, or —CH(CH₃)—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CF₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹¹ is methoxy, ethoxy, propoxy, butoxy, Cl, F, ═O, NR¹⁸R¹⁹, CF₃;     -   C₁-C₄ alkyl substituted with 0-1 R^(11a);     -   phenyl substituted with 0-3 R^(11b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3     R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl; -   R¹⁵, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, and butyl; -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁸, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and -   R¹⁹, at each occurrence, is independently selected from H, methyl,     and ethyl.

In another even more preferred embodiment the present invention provides

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R³ is R⁴, -   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a), -   R^(4a), at each occurrence, is independently selected from is     -   H, F, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   W is —CH₂—, or —CH(CH₃)—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;     -   C₁-C₄ alkyl substituted with 0-1 R^(10a);     -   phenyl substituted with 0-4 R^(10b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or     -   5 to 6 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br,     I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl; -   R¹⁵, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, and butyl; -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); and -   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,     4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,     (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,     propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or     ethoxyethyl.

In another even more preferred embodiment the present invention provides

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R³ is R⁴, -   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a), -   R^(4a), at each occurrence, is independently selected from is     -   H, F, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   W is —CH₂—, or —CH(CH₃)—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹¹ is methoxy, ethoxy, propoxy, butoxy, Cl, F, ═O, NR¹⁸R¹⁹, CF₃;     -   C₁-C₄ alkyl substituted with 0-1 R^(11a);     -   phenyl substituted with 0-3 R^(11b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(11b); -   R^(11a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3     R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl; -   R¹⁵, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, and butyl; -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁸, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and -   R¹⁹, at each occurrence, is independently selected from H, methyl,     and ethyl.

In another even more preferred embodiment the present invention provides

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R³ is R⁴, -   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-1 R^(4a), -   R^(4a), at each occurrence, is independently selected from is     -   H, F, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, —S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   W is —CH₂—, or —CH(CH₃)—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl; -   R¹⁵, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, and butyl; and -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl).

In another preferred embodiment the present invention provides

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, or 2; -   m is 0, 1, or 2; -   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, or butoxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, Br, I CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁶ is H, methyl, or ethyl; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, phenyl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H, methyl, ethyl, propyl, and     butyl; -   W is —(CR⁸R^(8a))_(p)—; -   p is 0, 1, or 2; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl and C₃-C₆     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-2 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, or 2; -   u is 0, 1, or 2; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl or C₃-C₆ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂, —S(═O)₂NR^(19b)—,     —NR^(19b)S(═O)—, or —S(═O)NR^(19b)—; -   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   B is a seven membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-1 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,         C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

In a more preferred embodiment the present invention provides

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R³ is R⁴, -   n is 0 or 1; -   m is 0 or 1; -   R⁴ is H, OH,     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-1 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   B is a seven membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;     -   C₁-C₄ alkyl substituted with 0-1 R^(10a);     -   phenyl substituted with 0-4 R^(10b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or     -   5 to 6 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, CF₃;     -   C₁-C₄ alkyl substituted with 0-1 R^(11a);     -   phenyl substituted with 0-3 R^(11b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3     R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,     4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,     (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,     propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or     ethoxyethyl; -   R¹⁸, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and -   R¹⁹, at each occurrence, is independently selected from H, methyl,     and ethyl.

In an even more preferred embodiment the present invention provides

-   B is

In a preferred embodiment the present provides

-   A is S; -   Q is —NR¹R²; -   R¹, at each occurrence, is independently selected from:     -   H;     -   C₁-C₆ alkyl substituted with 0-3 R^(1a);     -   C₂-C₆ alkenyl substituted with 0-3 R^(1a); -   R^(1a), at each occurrence, is independently selected from H, OR¹⁴,     F, ═O, NR¹⁵R¹⁶, CF₃;     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(1b);     -   phenyl substituted with 0-3 R^(1b); and     -   5 to 6 membered heterocycle substituted with 0-3 R^(1b); -   R^(1b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R² is independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆     alkoxy, phenoxy, and benzyloxy; -   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR¹⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C(═O)—(CR⁷R^(7a))_(m)—R⁴;     -   (CR⁷R^(7a))_(n)—NHC(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C(═O)NH—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—NHS(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—S(═O)₂NH—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, 2, or 3; -   m is 0, 1, 2, or 3; -   R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄ alkenyloxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₆ alkyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkenyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkynyl substituted with 0-3 R^(4a),     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, Br, I, CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁶ is H;     -   C₁-C₆ alkyl substituted with 0-3 R^(6a);     -   C₃-C₆ carbocycle substituted with 0-3 R^(6b); or     -   C₆-C₁₀ aryl substituted with 0-3 R^(6b); -   R^(6a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CF₃; -   R^(6b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, aryl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H and C₁-C₄ alkyl; -   W is —(CR⁸R^(8a))_(p)—; -   p is 0, 1, 2, 3, or 4; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, 2, or 3; -   u is 0, 1, 2, or 3; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,     —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or     —OC(═O)—; -   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   B is a 6, 7, or 8 membered thiolactam,     -   wherein the thiolactam is saturated, partially saturated or         unsaturated;     -   wherein each additional thiolactam carbon is substituted with         0-2 R¹¹; and,     -   optionally, the thiolactam contains a heteroatom selected from         —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-1 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,         C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₁-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

In a further preferred embodiment the present invention provides

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, or 2; -   m is 0, 1, or 2; -   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, or butoxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, Br, I CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁶ is H, methyl, or ethyl; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, phenyl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H, methyl, ethyl, propyl, and     butyl; -   W is —(CR⁸R^(8a))_(p)—; -   p is 0, 1, or 2; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl and C₃-C₆     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-2 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, or 2; -   u is 0, 1, or 2; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl or C₃-C₆ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,     —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, or —S(═O)NR^(19b)—; -   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   B is a seven membered thiolactam,     -   wherein the thiolactam is saturated, partially saturated or         unsaturated;     -   wherein each additional thiolactam carbon is substituted with         0-2 R¹¹; and,     -   optionally, the thiolactam contains a heteroatom selected from         —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-1 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,         C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   5 C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently-selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

In a further preferred embodiment the present invention provides

-   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0 or 1; -   m is 0 or 1; -   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, or butoxy; -   R⁴ is H, OH,     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-1 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, butoxy, or allyl; -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   R⁶ is H; -   R⁷, at each occurrence, is independently selected from H, F, CF₃,     methyl, and ethyl; -   R^(7a), at each occurrence, is independently selected from H, F,     CF₃, methyl, and ethyl; -   R^(7b) is independently selected from H, methyl, and ethyl; -   W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   B is a seven membered thiolactam,     -   wherein the thiolactam is saturated, partially saturated or         unsaturated;     -   wherein each additional thiolactam carbon is substituted with         0-2 R¹¹; and,     -   optionally, the thiolactam contains a heteroatom selected from         —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;     -   C₁-C₄ alkyl substituted with 0-1 R^(10a);     -   phenyl substituted with 0-4 R^(10b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or     -   5 to 6 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, CF₃;     -   C₁-C₄ alkyl substituted with 0-1 R^(11a);     -   phenyl substituted with 0-3 R^(11b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3     R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,     4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,     (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,     propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or     ethoxyethyl; -   R¹⁸, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and -   R¹⁹, at each occurrence, is independently selected from H, methyl,     and ethyl.

In a more preferred embodiment the present invention provides

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R³ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂(CH₃)₂,     —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃,     —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂,     —CH₂CH═C(CH₃)₂, —CH₂CH₂CH═CH₂, —CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂,     cis-CH₂CH═CH(CH₃), cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),     trans-CH₂CH₂CH═CH(CH₃); —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃),     cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,     cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,     cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—, phenyl-CH₂—,     (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,     (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,     (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,     (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,     (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,     (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,     (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl—F-phenyl)CH₂—,     phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,     (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—,     (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—,     (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—,     (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—,     (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,     (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,     (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,     (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,     (3-F-5-Cl-phenyl)CH₂CH₂—, or -   R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂(CH₃)₂, —CH₂CH₂CH₂CH₃,     —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃,     —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH(CH₂CH₃)₂,     —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH═CH₂,     —CH₂CH═CH₂, —CH═CHCH₃, cis-CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),     trans-CH₂CH═CH(C₆H₅), —CH₂CH═C(CH₃)₂, cis-CH₂CH═CHCH₂CH₃,     trans-CH₂CH═CHCH₂CH₃, cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃),     trans-CH₂CH═CHCH₂(C₆H₅), —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃),     —CH₂C≡C(C₆H₅) —CH₂CH₂C≡CH, —CH₂CH₂C≡C(CH₃), —CH₂CH₂C≡C(C₆H₅)     —CH₂CH₂CH₂C≡CH, —CH₂CH₂CH₂C≡C(CH₃), —CH₂CH₂CH₂C≡C(C₆H₅)     cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,     cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—, (3-CH₃-cyclobutyl)CH₂—,     cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—,     cyclohexyl-CH₂CH₂—, (2-CH₃-cyclopropyl)CH₂CH₂—,     (3-CH₃-cyclobutyl)CH₂CH₂—, phenyl-CH₂—, (2-F-phenyl)CH₂—,     (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, furanyl-CH₂—, thienyl-CH₂—,     pyridyl-CH₂—, 1-imidazolyl-CH₂—, oxazolyl-CH₂—, isoxazolyl-CH₂—,     phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,     (4-F-phenyl)CH₂CH₂—, furanyl-CH₂CH₂—, thienyl-CH₂CH₂—,     pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—,     isoxazolyl-CH₂CH₂—, -   W is a bond, —OCH₂—, or —CH(CH₃)—; -   X is a bond;

-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or     —N(CH₃)—, -   Z is phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl,     3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl,     2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl,     2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl,     3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl,     3-Cl—F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl,     2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl,     4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl,     thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl,     1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl,     cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl,     phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,     (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,     (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,     (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,     (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,     (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,     (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl—F-phenyl)CH₂—,     (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—,     (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—,     (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—,     (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—,     (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—,     (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—,     (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—,     (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—,     (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-piperidinyl)CH₂—,     phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—,     (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,     (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—,     (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—,     (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—,     (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,     (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,     (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,     (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,     (3-F-5-Cl-phenyl)CH₂CH₂—, (3-Cl—F-phenyl)CH₂CH₂—,     (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—,     (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—, (4-Me-phenyl)CH₂CH₂—,     (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—,     (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,     (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—,     (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,     (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,     (isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—, (cyclopropyl)CH₂CH₂—,     (cyclobutyl)CH₂CH₂—, (cyclopentyl)CH₂CH₂—, (cyclohexyl)CH₂CH₂—,     (morpholino)CH₂CH₂—, (N-piperidinyl)CH₂CH₂—, -   B is a seven membered thiolactam,     -   wherein the thiolactam is saturated, partially saturated or         unsaturated;     -   wherein each additional thiolactam carbon is substituted with         0-2 R¹¹; and,     -   optionally, the thiolactam contains a heteroatom selected from         —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,     (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,     (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,     (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,     (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—; -   R¹¹, at each occurrence, is independently selected from H, ═O,     methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,     (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,     (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,     (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,     (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—; and -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical.

In a further more preferred embodiment the present invention provides

-   B is

In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:

-   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(4-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2S,3R)     N1-[(3S)-hexahydro-1-(3-(2-tetrazolylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide; -   (2S,3R)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-napthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopent-ylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;     and -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;     and -   (2R,3S)     N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:

-   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobut-ylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl-]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;     and -   (2R,3S)     N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;     and -   (2R,3S)     N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:

-   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-di-hydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;     and -   (2R,3S)     N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide. -   (2R,3S)     N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;     and -   (2R,3S)     N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:

-   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-1-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-1-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;

(2R,3S) N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;

-   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-v)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;     and -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;     and -   (2R,3S)     N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:

-   (2R,3S)     N1-[(3S)-hexahydro-1-(3,3-diphenylpropyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(phenyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methoxy)-N4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methoxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(amino)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(butyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(2-furylmethyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(cyclopentyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;     and -   (2R,3S)     N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(cinnamyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide.

In another preferred embodiment of the present invention, Q is N(OH)H.

In another preferred embodiment of the present invention, Q is NH₂.

In another preferred embodiment

-   R³ is R⁴, -   R^(3a) is H, methyl, ethyl, propyl, or butyl; -   R⁴ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl -   R⁵ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl -   R^(5a) is H, methyl, ethyl, propyl, or butyl; and     the total number of carbon atoms in R³, R^(3a), R⁵ and R^(5a) equals     seven or more.

In another preferred embodiment

-   R³ is R⁴; -   R^(3a) is H; -   R⁴ is C₁-C₄ alkyl substituted with 1-2 R^(4a), -   R^(4a), at each occurrence, is independently selected from C₃-C₆     cycloalkyl substituted with 0-3 R^(4b), phenyl substituted with 0-3     R^(4b), or 5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₂-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); and -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy.

In another preferred embodiment

-   R³ is R⁴; -   R^(3a) is H; -   R⁴ is C₂-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a), -   R^(4a), at each occurrence, is independently selected from is     -   H, F, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₁-C₄ alkyl substituted with 1-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); and -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F. NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy.

In another preferred embodiment

-   W is —(CH₂)_(p)—; -   p is 1, 2, or 3; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);     -   wherein the 5 to 6 membered heterocycle does not contain an oxo         or imino substituted ring atom; and -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, —NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy.

In another preferred embodiment when R¹ is H, R² is hydroxy, and R¹¹ is H, then X is not a bond.

It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention.

In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.

In a third embodiment, the present invention provides a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).

In a preferred embodiment the neurological disorder associated with β-amyloid production is Alzheimer's Disease.

In a fourth embodiment, the present invention provides a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a metalloprotease inhibitor which inhibits γ-secretase activity.

In a preferred embodiment the neurological disorder associated with β-amyloid production is Alzheimer's Disease.

In a preferred embodiment, the metalloprotease inhibitor is a hydroxamic acid.

In a more preferred embodiment, the metalloprotease inhibitor is a hydroxamic acid with an IC₅₀ value of less than 10 μM in the Aβ immunoprecipitation assay.

In a fifth embodiment, the present invention provides a method for inhibiting γ-secretase activity for the treatment of a physiological disorder associated with inhibiting γ-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits γ-secretase activity.

In a preferred embodiment the physiological disorder associated with inhibiting γ-secretase activity is Alzheimer's Disease.

In a sixth embodiment, the present invention provides a compound of Formula (I) for use in therapy.

In a preferred embodiment the present invention provides a compound of Formula (I) for use in therapy of Alzheimer's Disease.

In a seventh embodiment, the present invention provides for the use of a compound of Formula (I) for the manufacture of a medicament for the treatment of Alzheimer's Disease.

DEFINITIONS

As used herein, the term “Aβ” denotes the protein designated Aβ, β-amyloid peptide, and sometimes β/A4, in the art. Aβ is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829. The 43 amino acid sequence is:

1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile Gly Leu Met Val Gly Gly Val Val 41 Ile Ala Thr. However, a skilled artisan knows that fragments generated by enzymatic degradation can result in loss of amino acids 1-10 and/or amino acids 39-43. Thus, an amino acid sequence 1-43 represents the maximum sequence of amino acids for Aβ peptide.

The term “APP”, as used herein, refers to the protein known in the art as b amyloid precursor protein. This protein is the precursor for Aβ and through the activity of “secretase” enzymes, as used herein, it is processed into Aβ. Differing secretase enzymes, known in the art, have been designated b secretase, generating the N-terminus of Aβ, a secretase cleaving around the 16/17 peptide bond in Aβ, and “γ secretases”, as used herein, generating C-terminal Aβ fragments ending at position 38, 39, 40, 41, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

When any variable (e.g., R^(5b)) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R^(5b), then said group may optionally be substituted with up to two R^(5b) groups and R^(5b) at each occurrence is selected independently from the definition of R^(5b). Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, “C₁-C₆ alkyl” denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.

Preferred “alkyl” group, unless otherwise specified, is “C₁-C₄ alkyl”.

As used herein, “alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of “C₂-C₆ alkenyl”, include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the like.

As used herein, “alkynyl” or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.

“Alkoxy” or “alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, “alkylthio” or “thioalkoxy” is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro. “Counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

“Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. “Haloalkoxy” is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like. “Halothioalkoxy” is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.

“Cycloalkyl” is intended to include saturated ring groups, having the specified number of carbon atoms. For example, “C₃-C₆ cycloalkyl” denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, “carbocycle” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred “carbocycle” are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term “heterocycle” or “heterocyclic ring” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms, preferably 1, 2, or 3 heteroatoms, independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, the term “aryl”, “C₆-C₁₀ aryl” or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Unless otherwise specified, “aryl” may be unsubstituted or substituted with 0 to 3 groups selected from H, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

The phrase “additional lactam carbons and thiolactam carbons”, as used herein, is intended to denote the number of optional carbon atoms in the lactam ring or thiolactam ring B of Formula (I). Formula (I″):

represents the lactam ring B of Formula (I). The ring numbering shown for lactams of Formula (I″) applies to analogous thiolactams. Additional lactam carbons are carbons in lactam ring B other than the carbons numbered 2 and 3 in the backbone of the formula. The additional lactam carbons may be optionally replaced by a heteroatom selected from oxygen, nitrogen and sulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional carbons, wherein one optional carbon may optionally be replaced by a heteroatom, such that the total number of members of lactam ring B, including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferred that the total number of atoms of lactam ring B is 6, 7 or 8; it is more preferred that the total number of atoms of lactam ring B is seven. Examples of lactam ring B include:

and their thiolactam counterparts. The examples are not intended to limit the invention. Preferred examples of lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferred examples of lactam ring B are B1, B6, B8, B9, and B13. Preferred examples of substituent R¹⁰ or R¹¹ on lactam B are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, and (4-trifluorophenyl)methyl.

The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula (I) may display superior chemical activity over the opposite enantiomer. For example carbon 3 of lactam ring B Formula (I″) may exist in either an S or R configuration. Thus, an R or S configuration at carbon 3 in Formula (I″) is considered part of the invention. An example of such configuration includes,

but is not intended to be limited to this example of ring B. When required, separation of the racemic material can be achieved by methods known in the art. Additionally, the carbon atoms to which R³ and R⁵ are attached may describe chiral carbons which may display superior chemical activity over the opposite enantiomer. For example, where R³ and R⁵ are not H, then the configuration of the two centers may be described as (2R,3R), (2R,3S), (2S,3R), or (2S,3S). All configurations are considered part of the invention; however, the (2R,3S) and the (2S,3R) are preferred and the (2R,3S) is more preferred.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

“Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.

“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

Synthesis

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.

Methods for the synthesis of succinylamino lactams are known in the art and are disclosed in a number of references including PCT publication number WO 96/29313, which is hereby incorporated by reference.

Disubstituted succinate derivatives can be prepared by a number of known procedures. The procedure of Evans (D. A. Evans et al, Org. Synth. 86, p 83 (1990)) is outlined in Scheme 1 where acylation of an oxazolidinone with an acylating agent such as an acid chloride provides structures 1. Alkylation to form 2 followed by cleavage of the chiral auxiliary and subsequent alkylation of the dianion of the carboxylic acid 3 provides a variety of disubstituted succinates which can be separated and incorporated into structures of Formula (I) by those skilled in the art. Additional examples are found in P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138, incorporated herein by reference.

Diastereomerically pure succinate derivatives can be accessed using the chemistry outlined below, adapted from P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138 incorporated herein by reference. This reference provides the synthesis below to obtain compound 9. Compound 11 is used as an intermediate and is prepared from 9 by hydrogenation of the allyl group followed by coupling of 9-fluorenemethanol under standard conditions using DCC and DMAP in CH₂Cl₂. Deprotection of the tert-butyl ester is accomplished by treatment with 50% trifluoroacetic acid.

Additional methods useful for the preparation of succinate derivatives are known by those skilled in the art. Such references include, McClure and Axt, Bioorganic & Medicinal Chemistry Letters, 8 (1998) 143-146; Jacobson and Reddy, Tetrahedron Letters, Vol 37, No. 46, 8263-8266 (1996); Pratt et al., SYNLETT, May 1998, p. 531; WO 97/18207; and WO 98/51665. The synthetic disclosures of WO97/18207 and WO 98/51665 are hereby incorporated by reference.

A variety of compounds of Formula (I) can be prepared by methods described in Scheme 4. The protected α-amine 3 of the α-amino-ε-caprolactam can be prepared by methods well known in the literature for amino protecting groups as discussed in Theodora W. Greene's book “Protective Groups in Organic Synthesis”, like N-Boc using di-t-butyldicarbonate in an appropriate solvent like DMSO. A sulfur atom can be introduced into the ring providing L-α-amino-β-thio-ε-caprolactam according to the procedure in S. A. Ahmed et al, FEBS Letters, (1984), vol. 174, pages 76-9 (Scheme 3). One skilled in the art can extend this methodology to the synthesis of β-amino and oxygen containing rings by analogy. The sulfur-containing molecules can also be oxidized to the sulfoxide and sulfone by methods known to one skilled in the art.

The lactam nitrogen of compound 13 can be alkylated by generating the anion with bases such as LDA, lithium bis(trimethylsilyl)amide or sodium hydride in solvents like THF, with or without cosolvents such as DMPU or HMPA and reacting this with a variety of groups containing leaving groups (X″) like bromide, iodide, mesylate or tosylate. Alkylating agents such as α-bromo amides, ketones and acids can be prepared by a number of literature methods including halogenation of amino acids by diazotization or are commercially available. Other suitable alkylating agents such as alkyl, allylic and benzylic halides can be formed form a variety of precursors such as free-radical addition of halides or activation of alcohols, and other chemistries known to those skilled in the art. For discussion of these types of reactions, see Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 304-305, 342-347, 695-698.

The N-Boc protecting group can be removed by any number of methods well known in the literature like TFA in methylene chloride to give the compound 15. The amine 15 can be coupled to an appropriately substituted carboxylic acid or acid chloride by methods well described in the literature for making amide bonds, like TBTU in DMF with a base like NMM to give the elaborated compound 16. Compounds 16 can be alkylated using standard bases like LDA, NaH, or NaHMDS to deprotonate the amide followed by addition of an alkylating agent with an appropriate leaving group like halide, mesylate, or triflate in an appropriate solvent to provide compounds 17 with an R⁶ substituent. The t-butyl ester is then removed by treatment with TFA in methylene chloride to give the carboxylic acid 17.

The final compounds 18 were prepared by treating the activated carboxylic acid of 17 with an appropriately substituted amine. For instance, activation of the carboxylic acid with HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) or PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) or other coupling agents known to those skilled in the art allows condensation with ammonia to form primary amides. Similarly, condensation of the activated acid with hydroxylamine hydrochloride provides the hydroxamic acid, or reaction with a primary or secondary amine provides the substituted amine derivative. Activation of the acid with PyBrOP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) followed by addition of an alcohol and 4-dimethylaminopyridine allows formation of the ester directly. For additional acylation reactions see for example Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 475-479.

Additional Examples of compounds of Formula (I) can be prepared as shown in Scheme 5. A suitable resin for solid phase synthesis such as Fmoc (Fluorenylmethylcarbonyl)-protected hydroxylamine bound to polystyrene beads can be purchased from Novabiochem, Inc. Deprotection of the Fmoc group under standard conditions using 20% piperidine in DMF provides trityl-linked hydroxylamine resin. Coupling of a fluorenylmethyl-protected succinic acid derivative such as 20 with a coupling agent such as HATU in a suitable solvent like DMF or N-methylpyrrolidinone provides the support-bound hydroxamate 21. The Fluorenylmethyl ester can be removed using 20% piperidine in DMF to provide the free carboxylic acid which can be coupled to amines like the caprolactam 22 (which is available using chemistry outlined in Scheme 4) using PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) and a suitable base like DIEA in DMF or NMP. The support-bound intermediate 23 can then be elaborated to biaryl structures of the type 24 using typical Suzuki coupling conditions employing a catalyst such as Palladium complexes like tetrakis(triphenylphosphine)-palladium with 2M aqueous sodium carbonate as a base in a suitable solvent like THF or DME and an excess of a boronic acid. The final compounds are liberated from the support employing dilute (5%) trifluoroacetic acid in CH₂CL₂ and purified by conventional chromatography.

General Procedure for Solid-Phase Synthesis According to Scheme 5.

Resin 20 of Scheme 5: Fmoc-protected resin 19 (2.0 g, 0.78 mmol/g, 1.56 mmol) is purchased from Novabiochem and swelled in 20 ml of CH₂Cl₂ for 1 hour. The CH₂Cl₂ is removed and the resin is then treated with 25% v/v piperidine in DMF (8 mL) and allowed to shake slowly for 16 h. The solvent was removed by filtration and the resin was shaken with an additional 8 mL of 25% v/v piperidine in DMF for 2 h at rt. The solvents were removed by filtration, and the resin 20 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂ and dried in vacuo.

Succinate 10 of Scheme 2: Succinate 9 is prepared according to the literature procedure (P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138). Succinate 9 (17.8 g, 66 mmol) is dissolved in 250 mL of ethyl acetate and placed in a Parr shaker bottle. To the solution is added 890 mg of 5% palladium on carbon, and the bottle is pressurized to 40 psi with hydrogen gas and shaken for 2.5 h at rt. The hydrogen is removed and the palladium catalyst is removed by filtration through a pad of celite. Concentration of the ethyl acetate solution provides 17.5 g (98%) of succinate 10. No further purification is necessary. MS (M−H)⁺=271.

Succinate 21 of Scheme 5: Succinate 10 (6.3 g, 23.1 mmol) is dissolved in 125 mL of CH₂Cl₂ and 4.8 g (23.3 mmol) of dicyclohexylcarbodiimide is added. The solution is stirred at rt for 30 min and then 4.6 g (23.4 mmol) of 9-fluorenemethanol is added followed by 122 mg (1 mmol) of 4-dimethylaminopyridine. After 5 h of stirring at rt, the reaction solution was diluted with an additional 100 mL of CH₂Cl₂ and filtered through a pad of celite to remove precipitated dicyclohexylurea. The solution was then washed 3× with 50 mL of a 1N HCl solution, 3× with 50 mL of a saturated sodium bicarbonate solution, and 2× with 50 mL of brine. The crude product was dried over MgSO₄ and concentrated onto 15 g of silica gel. Chromatography eluting with a gradient of 2.5% to 5% ethyl acetate/hexanes provided 6.4 g (61%) of the diester as an oil. The purified diester (6.4 g 14.2 mmol) is then dissolved in 25 mL of CH₂Cl₂, 25 mL of trifluoroacetic acid is added, and the reaction solution is stirred at rt for 2 h. The reaction solution is directly concentrated in vacuo to an oil which is then redissolved in 25 mL of toluene and reconcentrated, followed by drying in vacuo to provide 6.3 g (98%) of the desired succinate 9 as an oil which solidifies on standing. MS (M+Na)⁺=471, (M+2Na)⁺=439.

Caprolactam 23 of Scheme 5: Boc-caprolactam 14 (5.0 g 21.9 mmol) is dissolved in 60 mL of THF and chilled to −78° C. To the chilled solution is added 24 mL of a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF, and the solution was brought to 0° C. and stirred for 15 min. To the anion solution was added 6.5 g (22 mmol) of 3-iodobenzyl bromide (Aldrich) and the solution was allowed to warm to rt and stirred for 18 h. The reaction solution was diluted with 50 mL of water and extracted 3× with ethyl acetate. The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude product was purified by chromatography eluting with a gradient of 5-20% ethyl acetate/hexanes to afford 7.0 g (72%) of the title compound as a white solid. MS (M+Na)⁺=467.

Resin 22 of Scheme 5: Resin 22 (2.0 g, 0.78 mmol/g, 1.56 mmol) was swollen in 3 mL of DMF. In a separate flask, 1.85 g (4.68 mmol) of succinate 21 was dissolved in 3 mL of DMF and 2.5 mL of N,N-diisopropylethylamine (14 mmol) was added, followed by 1.81 g (4.68 mmol) of HATU. The solution containing the active ester was added to the slurried resin and the reaction suspension was slowly shaken for 18 h. The resin was then washed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. Loading of the resin was determined by Fmoc quantitation to be 0.25 mmol/g, see Reddy, M. P.; Voelker, P. J. Int. J. Pept. Protein Res. 1998, 31, 345-348.

Resin 24 of Scheme 5: Resin 22 (2.0 g, 0.25 mmol/g, 0.5 mmol) was suspended in 10 mL of 25% piperidine in DMF. The suspended resin was shaken for 30 min at rt, and then the resin was washed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. Deprotected resin (1.0 g, 0.25 mmol) was swollen in 2 mL of DMF. To the slurry was added 650 mg (1.25 mmol) of PyBOP and 217 mL (1.25 mmol) of DIEA. Separately, 443 mg (0.97 mmol) of caprolactam 23 was dissolved in 2 mL of DMF and 436 mL (2.5 mmol) of DIEA was added. The caprolactam solution was added to the resin slurry and the resin was mixed for 18 h at rt. The solvents were then removed and the coupling was repeated, with shaking at rt for 6 h. The resin was then washed 3× with 10 mL of DMF, 3× with 10 mL of methanol, and 3× with 10 mL of CH₂Cl₂.

Products 25 of Scheme 5: A 70 mg (17.5 mmol) portion of resin 24 was suspended in 1 mL of THF in a screw-cap vial. To the slurry was added a boronic acid (0.15 mmol), 150 mL of a 2 M solution of sodium carbonate, and 15 mg (13 mmol) of tetrakis(triphenylphosphine)palladium. The vial was tightly closed and heated to 60° C. for 16 h using a dry heater on a shaker table. The solvents were then removed by filtration and the resin was washed 3× with THF (2 mL), 3× with methanol (2 mL), 3× with water, and 3× with CH₂Cl₂. The resins were then placed in a glass vial and cleaved with 1 mL of 5% trifluoroacetic acid in CH₂Cl₂ for 30 min. The solution was filtered off and the resin was washed with an additional 2 mL of CH₂Cl₂ and the combined filtrates were evaporated to dryness to yield the crude products 25. The products were purified by chromatography eluting with 10-100% ethyl acetate in hexanes to yield 13.0 to 6.0 mg (14-60%) of the final products.

Additional Examples of compounds of Formula (I) can be prepared as shown in Scheme 6. A suitable resin for solid phase synthesis such as Fmoc (Fluorenylmethylcarbonyl)-protected peptide amide linker (PAL)-derivatized polystyrene beads can be purchased from Perkin Elmer Biosystems, Inc. Deprotection of the Fmoc group under standard conditions using 20% piperidine in DMF provides the free benzylamine. Coupling of a succinic acid derivative such as 28 (which is available using chemistry outlined in Scheme 4) with a coupling agent such as HATU in a suitable solvent like DMF or N-methylpyrrolidinone provides the support-bound amide 29. The support-bound intermediate 29 can then be elaborated to biaryl structures of the type 24 using typical Suzuki coupling conditions employing a catalyst such as Palladium complexes like tetrakis(triphenylphosphine)-palladium with 2M aqueous sodium carbonate as a base in a suitable solvent like THF or DME and an excess of a boronic acid. The final compounds are liberated from the support employing 50% trifluoroacetic acid in CH₂Cl₂ and can be purified by conventional chromatography or preparative HPLC.

General Procedure for Solid-Phase Synthesis According to Scheme 6

Resin 27 of Scheme 6: Fmoc-protected PAL resin 26 (0.80 g, 0.50 mmol/g, 0.40 mmol) is purchased from Advanced Chemtech and swelled in 20 ml of CH₂Cl₂ for 1 hour. The CH₂Cl₂ is removed and the resin is then treated with 25% v/v piperidine in DMF (6 mL) and allowed to shake slowly for 1 h. The solvents were removed by filtration, and the resin 27 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. and dried in vacuo.

Acid 28 of Scheme 6: To a solution of 0.100 g (367 mmol) of succinate 10 dissolved in 2.0 mL of dry DMF was added 0.120 mL (1.10 mmol) of N-methylmorpholine. A second solution containing 0.139 g (0.403 mmol) of caprolactam 23 of Scheme 5 dissolved in 2.0 mL of DMF was then added. To the mixed solution was added 229 mg (0.440 mmol) of PyBop and the reaction solution was stirred for 16 h at rt. The reaction solution was diluted with water (20 mL) and extracted 3× with 100 mL of ethyl acetate. The combined organic layers were dried with Na₂SO₄ and concentrated under reduced pressure. The resulting oil was purified by chromatography eluting with a gradient of 5-20% ethyl acetate in hexanes to provide 0.195 g (0.360 mmol, 98%) of the tert-butyl ester of Acid 28 (MS M+Na=621). The purified ester (0.195 g, 0.360 mmol) was dissolved in 10 mL of 25% trifluoroacetic acid in CH₂Cl₂ and stirred for 2 h at rt. The solvents were removed under reduced pressure and the acid was redissolved in 5 mL of toluene and reconcentrated 2× to remove residual TFA. The crude acid was found to be pure by ¹H NMR and was used in Scheme 6 without further purification.

Resin 29 of Scheme 6. Resin 27 (800 mg, 0.40 mmol) was solvated in 4.0 mL of dry DMF and 0.63 mL (3.6 mmol) of diisopropylethylamine was added followed by a solution of Acid 28 dissolved in 4 mL of DMF. To the slurry was then added 0.465 g (1.2 mmol) of HATU and the slurry was shaken for 26 h at rt. The solvents were removed by filtration, and the resin 29 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. and dried in vacuo.

Products 30 of Scheme 6: A 75 mg (0.38 mmol/g, 28.8 mmol) portion of resin 24 was suspended in 1 mL of THF in a screw-cap vial. To the slurry was added a boronic acid (0.33 mmol), 150 mL of a 2 M solution of sodium carbonate, and 15 mg (13 mmol) of tetrakis(triphenylphosphine)palladium. The vial was tightly closed and heated to 60° C. for 16 h using a dry heater on a shaker table. The solvents were then removed by filtration and the resin was washed 3× with THF (2 mL), 3× with methanol (2 mL), 3× with water, and 3× with CH₂Cl₂. The resins were then placed in a glass vial and cleaved with 1 mL of 5% trifluoroacetic acid in CH₂Cl₂ for 2 h. The solution was filtered off and the resin was washed with an additional 2 mL of CH₂Cl₂ and the combined filtrates were evaporated to dryness to yield the crude products 25. The products were purified by chromatography eluting with 10-100% ethyl acetate in hexanes to yield 0.5 to 2.0 mg (14-60%) of the final products.

The internal phenyl ring can be exchanged for a pyridine ring using chemistry outlined in Scheme 7. The chloromethyl pyridine 33 is prepared using a known procedure reported in Nutaitis, Charles F.; Ledeboer, Mark W. Org. Prep. Proced. Int. (1992), 24(2), 143-6 Incorporated herein by reference. After free basing the pyridine, alkylation with the Boc-caprolactam provides pyridine intermediate 34, which can be elaborated to the protected amide 35 with succinate 10. Substitution can then be introduced using Suzuki methodology employing a palladium source such as tetrakis(triphenylphosphine) palladium(0) or bis(diphenylphosphinoferrocene) palladium(II) dichloride and a suitable base such as sodium carbonate or triethylamine in a solvent such as THF or toluene containing 10% methanol. Stille chemistry is also possible using a suitable palladium source such as tetrakis(triphenylphosphine)palladium(0) and an aryl or vinyl tin derivative in a solvent such as benzene, toluene, or xylenes. The tert-butyl ester is then deprotected under standard acidic conditions using trifluoroacetic acid and the amide is formed under standard conditions to provide products 36.

General Procedure for Synthesis According to Scheme 7

The chloromethyl pyridine HCl salt 33 is prepared using a known procedure reported in Nutaitis, Charles F.; Ledeboer, Mark W. Org. Prep. Proced. Int. (1992), 24(2), 143-6.

Caprolactam 34: Pyridine HCl salt 33 (2.0 g, 8.3 mmol) is dissolved in 50 mL of a saturated NaHCO₃ solution and the solution is extracted with 30 mL of CH₂Cl₂ 3× followed by concentration of the organic layers to provide the free base. Separately, 1.8 g (7.8 mmol) of caprolactam 13 is dissolved in 40 mL of dry THF and chilled to −78° C. To the solution was added 8.7 mL of a 1M solution of sodium bis(trimethylsilyl)amide. The solution was brought to 0° C. and stirred for 30 min. To the resultant anion was added a solution of 1.7 g (8.3 mmol) of pyridine 33 free base dissolved in 40 mL of THF. The resulting reaction solution was stirred at rt for 18 h and then heated to 50° C. and stirred an additional 3 h. The reaction solution was allowed to cool and then 50 mL of water was added and the aqueous layer was extracted 2× with 100 mL of ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to provide the crude product which was purified by chromatography eluting with 20 to 100% ethyl acetate in hexanes to provide 1.5 g (51%) of caprolactam 34 as an oil.

Amide 35: Caprolactam 34 (0.40 g, 1.0 mmol) is dissolved in 20 mL of 50% trifluoroacetic acid in CH₂Cl₂ and stirred at rt for 30 min. The solvents were then removed under reduced pressure and the resulting oil was redissolved in 5 mL of toluene and reconcentrated to remove residual TFA. Separately, 0.270 g (1.0 mmol) of succinate 10 was dissolved in 5.0 mL of dry DMF and 0.44 mL (4 mmol) of N-methylmorpholine was added followed by 0.50 g (1.3 mmol) of HATU and the resulting solution was stirred at rt for 30 min. The crude deprotected caprolactam from above was dissolved in 5.0 mL of dry DMF and added to the succinate solution and the resulting solution was heated to 50° C. and stirred for 2 days. The solution was then diluted with 20 mL of water and extracted with 3 50 mL portions of ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to provide an oil which was purified by chromatography eluting with 20 to 50% ethyl acetate in hexanes to provide 0.40 g (70%) of the Amide 35.

Additional examples can be prepared by the method shown in Scheme 8. Coupling of an amine onto a commercially available aldehyde-derived resin 37 under conditions for reductive amination such as sodium tris(acetoxy)borohydride in CH₂Cl₂ containing 1% acetic provides a support-bound amine 38. The carboxylic acid 39 can then be coupled to the support-bound amine generating an amide 40 which can be liberated from the support employing trifluoroacetic acid in CH₂Cl₂.

General Procedure for Solid-Phase Synthesis According to Scheme 8

Resin 38 of Scheme 5: Aldehyde-derived resin 37 (200 mg, 0.5 mmol/g, 0.1 mmol) is purchased from Perkin Elmer Biosystems and swelled in 3 ml of CH₂Cl₂ for 1 hour. An amine (1.0 mmol), sodium tris(acetoxy)borohydride (106 mg, 0.5 mmol) and acetic acid (30 uL, 1%) are added and the reaction is shaken on a shaker table for 16 h at rt. The solvents were removed by filtration and the resin 38 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. and dried in vacuo.

Products 40 of Scheme 8: Carboxylic acid 39 (23 mg, 0.045 mmol), diisopropylethylamine (13 mL, 0.075 mmol) and HATU (17.1 mg, 0.045 mmol) were mixed in 0.5 mL of DMF for 30 min. Amine-derived resins 38 (30 mg, 0.015 mmol) were then added and the suspension was shaken at rt for 16 h. The solvents were removed by filtration and the resins were rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. The isolated resins were then cleaved by the addition of 0.50 mL of trifluoroacetic acid. The product solutions were concentrated and redissolved in 0.5 mL of methanol and reconcentrated 2× to remove residual TFA. Product yields ranged from 0-100%-based on the structure of the amine.

The compounds of Formula (I) of the present invention can also be prepared from aminolactam or aminothiolactam 42 and succinic acid derivatives 41 using amide bond syntheses known in the art, including methods commonly used in peptide syntheses, such as HATU, TBTU, BOP, pyBOP, EDC, CDI, DCC, hydroxysuccinimide, mixed carboxylic anhydride, and phenyl ester mediated couplings, as illustrated in Scheme 9 for the synthesis of aminolactam or aminothiolactam 43, an embodiment of the present invention.

Depending on the structure of the final product, it is appreciated by those skilled in the art that protecting groups or precursor functionality convertable to the desired groups may be desirable. Protecting groups and their use in synthesis are described in Green and Wuts, Protective Groups in Organic Synthesis, (Wiley 1991). The use of protecting groups is further illustrated in Scheme 10, in which the succinate half-ester 44 (Becket et al., Synlett 1993, 137-138) is coupled to the aminobenzodiazepine 45 (Sherrill and Sugg, J. Org. Chem. 1995, 60, 730-734; Bock et al., J. Med. Chem., 1993, 36, 4276-4292) to give ester 46, followed by conversion of the ester group to the primary amide 47.

Methods for the synthesis of lactams as contemplated by the present invention in lactam ring B in Formula (I), including amino benzodiazepines, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, which is hereby incorporated by reference. Additional references include Bock, et al, J. Org. Chem., 1987, 52, 3232-3239 and Sherrill et al, J. Org. Chem., 1995, 60, 730-734; Walsh, D. A., Synthesis, September 1980, p. 677.

The synthesis of the thiolactams of the present invention (Formula (I), A=S) can be carried out using thiolactam intermediates (42, A=S), using the methods described above. The thiolactam intermediates may be prepared from suitably protected aminolactams employing methods known to those skilled in the art, using, for example, Lawesson's reagent, P4S10, or related methods (see Taylor et al., Bioorg. Med. Chem. Lett. 1997, 7 (4), 453-456; Schwarz et al., Tetrahedron, 1997, 53 (26), 8795-8806; Achour et al., Synth. Commun. 1994, 24 (20), 2899-2905; Buege et al., Arch. Pharm. 1994, 327 (2), 99-103; Levai, et al., Arch. Pharm. 1992 (325 (11), 721-726; Duhammel et al., Tetrahedron Asymmetry 1991, 2 (3), 203-206; Bodine et al., Synth. Commun. 1982, 12, 787). Deprotection of the amine, coupling to an appropriate succinate derivative and elaboration of the distal succinic acid derivative provides the desired thiolactams of the present invention.

EXAMPLES

Chemical abbreviations used in the Examples are defined as follows: “DMPU” for 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, “TBTU” for O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and “BOP” for benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate. It is understood that one skilled in the art can discern compounds used in the synthesis of Examples of the invention may be referred to by structure and number. For example, Resin 20 refers to the resin of structure 20 in Scheme 5; succinate 9 refers to the structure 9 found in Scheme 2 which is a succinate compound.

“HPLC” is an abbreviation used herein for high pressure liquid chromatography. Reverse-phase HPLC was carried out using a Vydac C-18 column with gradient elution from 10% to 100% buffer B in buffer A (buffer A: water containing 0.1% trifluoroacetic acid, buffer B: 10% water, 90% acetonitrile containing 0.1% trifluoroacetic acid).

Example 1 (2R,3S) N1-[(3S)-hexahydro-1-(3,3-diphenylpropyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Step (1a): Di-tert-butyldicarbonate (10.2 g, 46.7 mmoles) was added portion wise to a solution of L-(−)-α-amino-ε-caprolactam (5.0 g, 39.0 mmoles) in dimethyl sulfoxide (30 mL). After 5 h at rt, the reaction was partitioned between water (100 mL) and ethyl acetate. The combined organic extracts were washed successively with 1 M HCl (50 mL), brine, and dried (MgSO₄) and concentrated in vacuo. The residue was recrystallized in 1:1 v/v ether-hexanes, two crops yielded the desired product (6.26 g, 70%) as white solid. MS (M+H—BOC)⁺=129.

Step (1b): Triphenylphosphine (3.0 g, 11.4 mmoles) and carbon tetrabromide (3.75 g, 11.7 mmoles) were added successively to a cooled (0° C.) solution of 3,3-biphenyl-1-propanol (1.5 mL, 7.5 mmoles) in dichloromethane (20 mL). After 1.5 hours at rt, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes) to give the desired product (1.93 g, 93% yield) as a clear oil. MS (M-BrC₂H₄)⁺=167

Step (1c): A 1.0 M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1.3 mL) was added over 15 minutes to compound of Step (1a) (0.29 g, 1.27 mmoles) in tetrahydrofuran (3 mL) and DMPU (2 mL) at −78° C. The iodo compound prepared from compound (1b) (0.85 g, 3.09 mmoles) by typical Finkelstein methodology, in tetrahydrofuran (4 mL) was added and the reaction was allowed to warm to rt slowly. This was stirred for 10 hours at ambient temperature, partitioned between water and ethyl acetate. The combined organic extracts were washed successively with water (20 mL), brine (20 mL), and dried (MgSO₄) and concentrated in vacuo. The resulting residue was purified by silica gel column (ethyl acetate:hexanes, 5:95 then ethyl acetate:hexanes, 15:85) to give the desired product (0.16 g, 30%). MS (M-Ot-Bu)⁺=349.

Step (1d): Trifluoroacetic acid (3 mL) was added to a solution of compound of Step (1c) (0.16 mg, 0.38 mmoles) in dichloromethane (9 mL). After 2 h at rt, the solvent was removed in vacuo. The residual trifluoroacetic acid was removed by azeotrope with dichloromethane (50 mL), toluene (50 mL), and dichloromethane (50 mL) successively to give the desired product (0.17 g, 99%) as a yellow oil. MS (M+H)⁺=323.

Step (1e): 4-Methylmorpholine (0.6 mL, 5.46 mmoles) and TBTU (0.11 g, 0.34 mmoles) were added to a solution of succinate acid (P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138) (0.085 g, 0.31 mmoles) in N,N-dimethylformamide (3 mL). After 30 minutes at rt, the compound from step (1d) (0.17 g, 0.39 mmoles) was added to the mixture. The reaction was stirred for 16 h at rt, then partitioned between 1 M HCl (20 mL) and ethyl acetate. The combined organic extracts were washed successively with saturated aqueous sodium bicarbonate (20 mL), water (20 mL), brine (20 mL), dried (MgSO₄) and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexanes, 7:93 gradient to ethyl acetate:hexanes 25:75) to give the desired product (120 mg, 67%) as a clear oil. MS (M+NH₄-Ot-Bu)⁺=521.

Step (1f): Trifluoroacetic acid (3 mL) was added to a solution of compound of Step (1e) (120 mg, 0.21 mmoles) in dichloromethane (9 mL). After 3 hours at rt, the mixture was concentrated in vacuo. The residual trifluoroacetic acid was removed by azeotrope with toluene (1×50 mL) and dichloromethane (1×50 mL). The residue was triturated with Et₂O:Hexanes 95:5, to give the desired product (75 mg, 70%) as a white solid. MS (M−H)-=519.

Step (1g): 4-Methylmorpholine (0.05 mL, 0.45 mmoles) and BOP (73 mg, 0.17 mmoles) were added to a solution of compound of Step (1f) (60 mg, 0.12 mmoles) in N,N-dimethylformamide (2 mL). Hydroxylamine (33 mg, 0.47 mmoles) was added to the mixture, the reaction was stirred for 16 h at rt, was concentrated in vacuo, was acidified with trifluoroacetic acid, then purified by reverse phase HPLC on a Vydac C-18 column, to give the desired hydroxamic acid as a white solid (45 mg, 75%). MS (M−H)-=534.

Example 2 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Step (2a): Triphenylphosphine (3.40 g, 13.0 mmoles) and carbontetrabromide (4.20 g, 13.0 mmoles) were added successively to a solution of m-phenoxybenzyl alcohol (1.5 mL, 8.6 mmoles). After 4 h at rt the mixture was concentrated and was purified by silica gel column (hexanes, then ethyl acetate:hexanes, 5:95) to give the desired bromide (1.3 g, 57%) as a yellow oil. MS (M-Br)⁺=183.

Step (2b): A 1 M solution of lithium bis(trimethylsilyl)amide was added dropwise to a solution of compound of Step (1a) (0.3 g, 1.31 mmoles) in tetrahydrofuran (5 mL) at −78° C. After 30 minutes a solution of compound of Step (2a) (0.43 g, 1.63 mmoles) in tetrahydrofuran (4 mL) was added to the mixture dropwise. The reaction was allowed to come to ambient temperature, stirred for 16 h, then partitioned between water and ethyl acetate. The combined organic extracts were washed successively with water (20 mL), brine (20 mL), dried (MgSO₄) and concentrated in vacuo. The crude residue was purified by silica gel chromatography (ethyl acetate:hexanes, 5:95 then ethyl acetate:hexanes, 15:85) to give the desired product (360 mg, 67%) as a clear oil. MS (M-Ot-Bu)⁺=337.

Step (2c): Trifluoroacetic acid (5 mL) was added to a solution of compound of Step (2b) in dichloromethane (15 mL). After 3 h at rt the solution was concentrated in vacuo. The residual trifluoroacetic acid was removed from residue by azeotrope with toluene (50 mL) then dichloromethane (30 mL) to yield the desired amine (390 mg, 99%) as a clear oil. MS (M+H)⁺=311.

Step (2d): Following a procedure analogous to the preparation of Step (1e), but using the compound from of Step (2c) (390 mg, 0.88 mmoles) the amide was prepared, The crude compound was purified by silica gel chromatography to give the desired product (0.38 g, 92%) as a yellow oil. MS (M-Ot-Bu)⁺=491.

Step (2e): Following a procedure analogous to the preparation of step (1f), but using the compound from Step (2d) (380 mg, 0.67 mmoles), the carboxylic acid was prepared. The product was precipitated from ethyl ether with hexanes, to give the desired acid (227 mg, 66%) as a white solid. MS (M−H)⁻=507.

Step (2f): Following a procedure analogous to the preparation of compound of Step (19), but using the compound from step (2e) (150 mg, 0.29 mmoles) the title compound was prepared. The crude was purified by reverse phase HPLC on a Vydac C-18 column to give the desired product (90 mg, 58%) as a white solid. MS (M−H)⁻=522.

Example 3 (2R,3S) N1-[(3S)-hexahydro-1-(phenyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Step (3a): Triethylamine (1.5 mL, 10.8 mmoles), copper (II) acetate (0.95 g, 5.2 mmoles) and phenylboric acid (1.6 g, 13.1 mmoles) were added successively to a solution of compound of Step (1a) (1.0 g, 4.4 mmoles) in dichloromethane (20 mL). After 2.5 h at rt, more phenylboric acid (0.5 g, 4.1 mmoles) was added to the mixture. After an additional 3 hours at rt more phenylboric acid (0.5 g, 4.1 mmoles) was added to the mixture. After 65 h at rt, the mixture was filtered over celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (ethyl acetate:hexanes, 5:95 then 15:85) to give the desired product (250 mg, 19%). MS (M-Ot-Bu)⁺=231.

Step (3b): Following a procedure analogous to the preparation of compound of Step (2c), but using compound of Step (3a) (250 mg, 0.82 mmoles), the amine (300 mg, 99%) was prepared as a yellow oil. MS (M+H)⁺=205.

Step (3c): Following a procedure analogous to the preparation of compound of Step (1e), but using compound from Step (3b) (0.3 g, 0.94 mmoles), the amide was prepared. The residue was purified by silica gel chromatography (ethyl acetate:hexanes, 5:95 to 20:80 in 5% increments, 500 mL each ratio) to give the desired product (210 mg, 60%) as a clear oil. MS (M+H-t-Bu)⁺=403.

Step (3d): Following a procedure analogous to the preparation of compound of Step (1f), but using compound from Step (3c) (200 mg, 0.44 mmoles) the acid was prepared. The crude oil was triturated with ether:hexanes 1:1 to give the desired acid (114 mg, 65%) as a white solid. MS (M−OH)⁺=385.

Step (3e): Following a procedure analogous to the preparation of compound of Step (1g), but using compound from Step (3d) (82 mg, 0.20 mmoles) the title compound was prepared. The crude product was purified by reverse phase HPLC on a Vydac C-18 column to give the desired product (80 mg, 94%). MS (M−H)⁻=416.

Example 4 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 3, compound of Step (2e) (100 mg, 0.20 mmol) was treated with HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) (114 mg, 0.30 mmol) and N-methyl morpholine (66 mL, 0.6 mmol) in 2 mL of DMF for 15 min at rt. A solution of 2.0 M methylamine in THF (0.2 mL, 0.4 mmol) was added and the reaction solution was stirred for 1 h at rt. The reaction solution was diluted with 1N HCl (5 mL) and extracted 3× with 10 mL of ethyl acetate. The combined organic layers were washed with a saturated sodium bicarbonate solution (5 mL) and brine (5 mL), dried over magnesium sulfate, and concentrated in vacuo to provide the crude amide. Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)⁺=544.

Example 5 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methoxy)-N4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with N,O-dimethylhydroxylamine hydrochloride (40 mg, 0.40 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)⁺=574.

Example 6 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methoxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with O-methylhydroxylamine hydrochloride (40 mg, 0.40 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)⁺=560.

Example 7 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with a 2.0 M solution of ammonia in dioxane (0.2 mL, 0.4 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)⁺=530.

Example 7A (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(amino)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with hydrazine (13 mg, 0.4 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (11.1 mg, 21%). MS (M+Na)⁺=542.

Example 8 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

(8a) Compound 8a was synthesized following a procedure analogous to the preparation of the compound 1e, but using the caprolactam 2c (2.5 g, 5.89 mmol), succinate 9 (1.64 g, 6.0 mmol), and HATU instead of TBTU. The compound was purified by chromatography eluting with 5% methanol in CH₂Cl₂ to afford 1.50 g (45%) of the desired ester.

(8b) The ester from 8a (1.18 g, 2.10 mmol) was dissolved in 10 mL of a 50% solution of trifluoroacetic acid in CH₂Cl₂ and stirred at rt for 2 h. The solvents were removed by concentration under reduced pressure and the crude product was dissolved in 10 mL of toluene and reconcentrated twice to remove residual TFA. The crude acid was used without further purification or characterization.

Following a procedure analogous to the preparation of Example 7, compound 8b (1.065 g, 2.10 mmol) was activated and condensed with an excess of gaseous ammonia. Purification by reverse phase HPLC on a Vydac-18 column provided 500 mg (47%) of the desired compound of Example 8. MS (M+Na)⁺=528.

Example 9 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(allyl)-butanediamide

Example 9 was synthesized following a procedure analogous to the preparation of Example 2, but using succinate 9 (Scheme 2). Purification by reverse phase HPLC on a Vydac-18 column provided 150 mg of Example 9. MS (M+Na)⁺=544.

Example 10 (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 2,4-dichlorophenyl boronic acid. Purification afforded 6.0 mg (60%) of the desired product. MS (M+Na)⁺=598.

Example 11 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 4-fluorophenyl boronic acid. Purification afforded 5.0 mg (54%) of the desired product. MS (M+Na)⁺=548.

Example 12 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 4-methylphenyl boronic acid. Purification afforded 3.0 mg (33%) of the desired product. MS (M+Na)⁺=544.

Example 13 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 4-methoxyphenyl boronic acid. Purification afforded 3.0 mg (32%) of the desired product. MS (M+Na)⁺=560.

Example 14 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 3-methylphenyl boronic acid. Purification afforded 3.0 mg (33%) of the desired product. MS (M+Na)⁺=544.

Example 15 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 3-chloro-4-fluorophenyl boronic acid. Purification afforded 4.0 mg (41%) of the desired product. MS (M+Na)⁺=582.

Example 16 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 4-trifluoromethylphenyl boronic acid. Purification afforded 4.0 mg (40%) of the desired product. MS (M+Na)⁺=598.

Example 17 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 3-methoxyphenyl boronic acid. Purification afforded 4.1 mg (44%) of the desired product. MS (M+Na)⁺=560.

Example 18 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 3-fluorophenyl boronic acid. Purification afforded 3.5 mg (38%) of the desired product. MS (M+Na)⁺=548.

Example 19 (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 2-methoxyphenyl boronic acid. Purification afforded 1.3 mg (14%) of the desired product. MS (M+Na)⁺=560.

Example 20 (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 2-naphthyl boronic acid. Purification afforded 3.0 mg (31%) of the desired product. MS (M+Na)⁺=580.

It will be understood by one skilled in the art that Scheme 6 can be followed in a manner analogous to the procedure for Scheme 5.

Example 21 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-methoxyphenyl boronic acid. Purification afforded 0.5 mg of the desired product. MS (M+Na)⁺=544.

Example 22 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 3-fluorophenyl boronic acid. Purification afforded 1.6 mg of the desired product. MS (M+Na)⁺=532.

Example 23 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-trifluoromethylphenyl boronic acid. Purification afforded 0.7 mg (4.3%) of the desired product. MS (M+Na)⁺=582.

Example 24 (2R,3S) N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 2,6-dichlorophenyl boronic acid. Purification afforded 1.8 mg (11%) of the desired product. MS (M+Na)⁺=582.

Example 25 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-tolyl boronic acid. Purification afforded 1.8 mg (12%) of the desired product. MS (M+Na)₊=528.

Example 26 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-methoxyphenyl boronic acid. Purification afforded 0.5 mg (3.3%) of the desired product. MS (M+Na)⁺=544.

Example 27 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-fluoro-3-chlorophenyl boronic acid. Purification afforded 0.5 mg (3.3%) of the desired product. MS (M+Na)⁺=567.

Example 28 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 2-methoxyphenyl boronic acid. Purification afforded 0.8 mg (5.3%) of the desired product. MS (M+Na)⁺=544.

Example 29 (2R,3S) N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 2-methoxyphenyl boronic acid. Purification afforded 1.5 mg (10%) of the desired product. MS (M+Na)⁺=544.

It will be understood by one skilled in the art that Scheme 7 can be followed in a manner analogous to the procedure for Schemes 5 and 6.

Example 30 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

Amide 35 of Scheme 7 (0.10 g, 0.18 mmol) was dissolved in 5 mL of toluene and 41 mg (0.27 mmol) of 4-methoxyphenyl boronic acid was added, followed by 31 mg (0.147 mmol) of tetrakis(triphenylphosphine)palladium, 0.5 mL of a 2M sodium cabonate solution and 0.5 mL of methanol. The reaction solution was heated to reflux for 16 h and then allowed to cool to rt. The reaction solution was diluted with 10 mL of water and extracted 2× with 50 mL of ethyl acetate. The combined organic layers were dried and concentrated and the resulting oil was purified by chromatography eluting with 30 to 100% ethyl acetate in hexanes as a solvent to provide 30 mg (29%) of biaryl product. MS (M+H)⁺=580.

The purified biaryl product was dissolved in 10 mL of 1:1 trifluoroacetic acid/CH₂Cl₂ and stirred at rt for 2 h. The solvents were then removed under reduced pressure and the resulting oil was redissolved in 5 mL of toluene and reconcentrated to remove residual TFA. The crude acid (25 mg, 0.047 mmol) was then dissolved in 1 mL of DMF and 10 mL of N-methylmorpholine (0.094 mmol) and 42 mg (0.062 mmol) HATU were added and the reaction solution was stirred at rt for 45 min. Gaseous ammonia was then bubbled in at a gentle rate for about 1 minute and the solution was stirred for an additional 1 min. The reaction solution was then diluted with 10 mL of water and extracted 3× with 30 mL of ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to a solid which was purified by reversed phase HPLC to provide 3.5 mg (10%) of the compound of Example 30 as its trifluoroacetic acid salt. MS (M+H)⁺=523.

Example 31 (2R,3S) N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for the compound of Example 30 was followed using 4-trifluoromethylphenyl boronic acid. Purification by HPLC afforded 6.0 mg of the desired product from as its trifluoroacetic acid salt. MS (M+Na)⁺=583.

Example 32 (2R,3S) N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

Amide 35 (0.30 g, 0.54 mmol) was dissolved in 3 mL of DMF and 123 mg (0.70 mmol) of 4-methoxyphenyl boronic acid was added, followed by 44 mg (0.0543 mmol) of bis(diphenylphosphinoferrocene) palladium (II) dichloride and 1.0 mL (7.18 mmol) of triethylamine. The reaction solution was heated to 80° C. for 24 h and then allowed to cool to rt. The reaction solution was diluted with 10 mL of water and extracted 2× with 50 mL of ethyl acetate. The combined organic layers were dried and concentrated and the resulting oil was purified by chromatography eluting with 20 to 100% ethyl acetate in hexanes as a solvent to provide 140 mg (50%) of biaryl product. MS (M+Na)⁺=624.

The general procedure reported for the compound of Example 30 was then followed to provide the amide. Purification by chromatography eluting with 20 to 100% ethyl acetate in hexanes afforded 45 mg of the desired product of Example 32 as its trifluoroacetic acid salt. MS (M+Na)⁺=567.

Example 33 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(butyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed using butylamine. Analysis by ¹HNMR integration relative to an internal standard revealed a yield of 100% of the desired product. MS (M+Na)⁺=586.

Example 34 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(2-furylmethyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed using 2-furylmethylamine. Analysis by ¹HNMR integration relative to an internal standard revealed a yield of 75% of the desired product. MS (M+Na)⁺=610.

Example 35 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(cyclopentyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme, 8 was followed using cyclopentylamine. Analysis by ¹HNMR integration relative to an internal standard revealed a yield of 42% of the desired product. MS (M+Na)⁺=598.

Example 36 (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(cinnamyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed using cinnamylamine. Analysis by ¹HNMR integration relative to an internal standard revealed a yield of 100% of the desired product. MS (M+Na)⁺=646.

Example 37 (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide

3-Bromomethylbenzophenone. A solution of 3-methylbenzophenone (20 g, 102 mmol) dissolved in 40 mL of 1,2-dibromoethane was heated to reflux. Over a period of about 3 hours a solution of 105 mmol of bromine dissolved in 6 mL of 1,2-dibromoethane was added to the refluxing solution. After the addition was complete the solution was allowed to cool to rt and diluted with 100 mL of dichloromethane. The organic layer was extracted with 1×25 mL of 1 N HCl, 2×15 mL of NaHCO₃ Solution, and 2×25 mL of brine. The organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was then distilled to afford the product, 16.5 g (60%) as an oil that solidified upon standing, b.p. 160° C. at 300 mTorr. ¹H NMR analysis shows that the product contains approximately 7% of the dibromide.

3-(1,1-dimethylethylcarbomethoxy-N-(benzophenone-3-yl-methyl)caprolactam. Diisopropylamine (4.2 mL, 30 mmol) was dissolved in 25 mL of THF and chilled to −78° C. To the solution was added 10 mL of 2.5M n-butyllithium in hexanes and the solution was warmed to 0° C. and allowed to stir for 10 min. A solution of Boc-protected aminocaprolactam 1a (5.0 grams, 22 mmol) dissolved in 25 mL of THF was then added and the reaction solution was stirred for 1 h at 0° C. Solid 3-bromomethyl-benzophenone was then added and the reaction solution was allowed to warm to rt and stir overnight. The reaction solution was diluted with water and extracted into ethyl acetate (100 mL). The organic layer was rinsed with 2×25 mL of 1 N HCl, 2×25 mL of saturated NaHCO₃ and 2×25 mL of brine, dried over magnesium sulfate, and dried in vacuo. Chromatography eluting with a gradient of 30% to 40% ethyl acetate in hexanes afforded the pure benzophenone-substituted caprolactam derivative (7.4 g, 80%). MS (M+Na)⁺=445.

The compound of Example 10 was synthesized in a manner analagous to the synthesis of the compound of Example 8 using succinate 9 and the benzophenone-substituted caprolactam derivative. The compound was purified by crystallization from ethyl acetate to afford 0.26 g of crystals. MS (M+Na)+=540.

Example 38 (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The compound of Example 11 was synthesized in a manner analagous to the synthesis of the compound of Example 8 using succinate 10 and the benzophenone-substituted caprolactam derivative. The compound was purified by crystallization from ethyl acetate to afford 0.25 g of crystals. MS (M+Na)+=542.

Example 39 (2R,3S) N1-[(3S)-hexahydro-1-(4-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

(39-a) 3-(1,1-dimethylethylcarbomethoxy-N-(4-bromophenylmethyl)caprolactam. The title compound was synthesized in a manner analogous to the preparation of 3-(1,1-dimethylethylcarbomethoxy-N-(benzophenone-3-yl-methyl)caprolactam in Example 10 but using 4-bromobenzyl bromide as the alkylating agent. The compound was purified by chromatography eluting with 5-20% ethyl acetate in hexanes as eluent to provide 7.0 g (70%) of the title compound as a solid. MS (M+Na)+=419.

(39-b) 3-(1,1-dimethylethylcarbomethoxy-N-(4,-(4′-trifluoromethylphenyl)phenylmethyl)caprolactam. To a solution of 3-(1,1-dimethylethylcarbomethoxy-N-(4-bromophenylmethyl)caprolactam (0.5 g, 1.26 mmol) dissolved in 10 mL of toluene was added 263 mg (1.38 mmol) of 4-trifluoromethylphenyl boronic acid, 1 mL of methanol, and 1 mL of a 2M solution of potassium carbonate. The solution was degassed by nitrogen bubbling for 5 min, and then 33 mg of tris(dibenzylideneacetone)dipalladium (0) chloroform adduct and 66 mg of triphenylphosphine was added. The solution was heated to reflux for 16 h and then allowed to cool and diluted with 20 mL of water. The aqueous layer was extracted 3× with 25 mL of ethyl acetate and concentrated. The resulting oil was purified by chromatography eluting with 20% ethyl acetate in hexanes to afford 0.47 g (81%) of an oil which crystallized on standing.

(39-d) The compound 39-d was synthesized in a manner analagous to the synthesis of the compound of Example 8 using succinate 10 (280 mg, 1.04 mmol) and 3-(1,1-dimethylethylcarbomethoxy-N-(4,-(4′-trifluoromethylphenyl)-phenylmethyl)caprolactam. The compound was purified by chromatography eluting with 20-100% ethyl acetate in hexanes to afford 40 mg of a white powder. MS (M+H)+=560.

Example 40 (2S,3R) N1-[(3S)-hexahydro-1-(3-(2-tetrazolylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide

(40-a) The compound of Example 40 was synthesized in a manner analogous to the synthesis of the compound of Example 39, but using the substituted acid 28 of Scheme 6 (50 mg, 0.10 mmol) and o-((N-trityl)-tetrazole)phenylboronic acid under the conditions for the formation of the compound (39-b). The desired biaryl acid was isolated as an impure mixture (134 mg) and used directly in the next step.

(40-b) The acid 40-a (134 mg, impure mixture) was converted to the amide under the conditions reported for the compound of Example 8. The crude amide was then dissolved in 2 mL of 10% trifluoroacetic acid in methanol and allowed to stir at rt for 30 min. The solvents were removed and the residue was purified by chromatography eluting with 10% methanol in ethyl acetate to provide 40 mg (71%, 2 steps) of the compound of Example 40 as a sticky powder. MS (M+Na)+=582.

Example 41 (2S,3R) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide

(41-a) The compound of Example 41 is formed by coupling Succinate 23 (480 mg, 1.21 mmol) with the substituted caprolactam TFA salt 2c under the conditions reported for the synthesis of the compound of Example 8. The crude fluorenylmethyl ester was used in the next step with out further purification. MS (M+Na)+=709.

(41-b) The crude fluorenylmethyl ester is dissolved in 2 mL of a 50% solution of piperidine in CH₂Cl₂ and stirred for 3 h at rt. A 10 mL portion of 1N HCl was then added and the mixture was extracted 3× with 10 mL of ethyl acetate. The crude acid was used in the next step with out further purification. MS (M+H)+=509.

The compound of Example 41 was then prepared using the acid 41-b under the conditions reported for compound of Example 28. The compound was purified by chromatography eluting with 5% methanol in CH₂Cl₂ to afford 120 mg (19%, 3 steps) of a white powder. MS (M+H)+=508.

Example 42 (2S,3R) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide

3-Phenoxybenzyl iodide: To a solution of 3-phenoxybenzyl chloride (10.0 g, 45.7 mmol) in 200 ml acetone was added sodium iodide (7.6 g, 507 mmol). The mixture was stirred at temperature overnight. The mixture was diluted with 300 ml hexane and the organic layer was washed twice with 5% sodium bicarbonate, once with brine and then dried over MgSO₄. Evaporation of the filtrate gave a light yellow oil. The product was used in next step without purification. ¹H NMR (CDCl₃) 4.4 (s, 2H), 6.8-7.4 (m, 9H).

Synthesis of Example 42

To a solution of benzodiazepine 50 (910 mg, 3.63 mmol), succinate 9 (980 mg, 3.63 mmol), hydroxybenzotriazole (980 mg., 7.25 mmol) and EDC (870 mg, 4.54 mmol) in 100 ml CH₂Cl₂ at 0 degrees was added triethylamine (0.76 ml, 5.45 mmol), The reaction mixture was washed with saturated sodium bicarbonate solution, 1.0N HCl, brine and dried over MgSO₄. Evaporation of the organic layer and purification by column chromatography on silica gel with hexane-ethyl acetate (7:3) gave 610 mg of benzodiazepine 51 as a white solid. M+H=504.37. ¹H NMR (CDCl₃) 0.8-1.0 (m, 6H), 1.0-1.2 (m, 1H), 1.4-1.5 (d, 9H), 1.6-1.9 (m, 2H), 2.2-2.8 (m, 4H), 4.9-5.2 (m, 2H), 5.6 (dd, 1H), 5.6-6.0 (m, 1H), 7.0-7.6 (m, 9H).

To a solution of benzodiazepine 51 (440 mg, 0.875 mmol) in DMF (20 ml) at 0 degrees was added NaH (45 mg, 1.12 mmol). The mixture was stirred at 0 degrees for 1.5 hr and then a solution of 3-phenoxylbenzyl iodide (330 mg, 1.06 mmol) in 10 ml DMF was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC using hexanes:EtOAc 6:4 (product Rf=0.31) indicated that the reaction was complete. The reaction mixture was quenched with water, and the solvent was evaporated under high vacuum, which provided a viscous yellow oil. The product benzodiazepine 52 was dissolved in ethyl acetate, which was washed with water (2×), brine and then dried over MgSO₄.

Evaporation of solvent gave 600 mg of benzodiazepine 52 as a yellow oil which was not further purified. M+H=686.3, M+Na=708.3. ¹H NMR (CDCl₃) 0.8-1.0 (m, 6H), 1.0-1.3 (m, 1H), 1.4-1.5 (d, 9H), 1.5-1.9 (2H), 2.2-2.7 (4H), 4.6-4.8 (d, 1H), 4.9-5.2 (m, 2H), 5.6-5.9 (m, 3H), 6.6-7.6 (m, 18H).

A solution of benzodiazepine 52 in 40 ml of TFA/CH₂Cl₂ (1:1) was stirred overnight at room temperature then evaporated to dryness. Repeated addition of toluene and evaporation provided 560 mg. of 53 as a yellow solid. (M−H=629.1)

To a solution of benzodiazepine 53 and HATU (410 mg, 1.08 mmol) in 30 ml DMF was added diisopropylethylamine (0.6 ml, 3.44 mmol) at 0 degrees. After 10 minutes, ammonia gas was bubbled through the solution for two minutes, and the reaction mixture was allowed to warm to room temperature and stirred overnight. Addition of water and solvent evaporation under high vacuum provided a yellow solid. The solid was taken up in ethyl acetate-water (1:1), and the organic layer was washed with water (2×), brine and then dried over MgSO₄. Evaporation of solvent gave a light yellow solid. Chromatographic purification on silica gel using CH₂Cl₂:methanol (10:0.5) gave 256 mg of Example 42. M+H=629.2 HNMR (CDCl₃) 0.8-1.0 (m, 6H), 1.2-1.4 (m, 1H), 1.6-2.0 (m, 2H), 2.2-2.8 (4H), 4.6-4.8 (m, 1H), 5.0-5.2 (m, 2H), 5.6-5.9 (m, 3H), 6.2-7.8 (m, 18H).

Example 43 (2R) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-butanediamide

Step (43a): The compound of Step (43a) is formed by coupling succinate 7 (115 mg, 0.5 mmol) with the substituted caprolactam TFA salt (212 mg, 0.5 mmol) from Step (2c) of Example 2 under the conditions reported for the synthesis of the compound of Example 8. The crude tert-butyl ester was taken on without further purification.

Step (43b): The compound of Step (43b) is formed by dissolving the crude product from Step (43a) in 5 mL of a 1:1 solution of TFA/CH₂Cl₂ and stirring at room temperature for 2 hours. Concentration followed by reconcentration twice from 10 mL of toluene provides the crude acid which was taken on with no further purification.

Step (43c): The title compound, Example 43, was prepared using the acid from Step (43b) under the conditions reported for the compound of Example 7. The compound was purified by chromatography eluting with 5% methanol in CH₂Cl₂ to afford 50 mg (21%, 3 steps) of a white powder. MS (M+Na)⁺=488.

Utility

Aβ production has been implicated in the pathology of Alzheimer's Disease (AD). The compounds of the present invention have utility for the prevention and treatment of AD by inhibiting Aβ production. Methods of treatment target formation of Aβ production through the enzymes involved in the proteolytic processing of β-amyloid precursor protein. Compounds that inhibit b or g secretase activity, either directly or indirectly, control the production of Aβ. Such inhibition of β or γ secretases reduces production of Aβ, and is expected to reduce or prevent the neurological disorders associated with Aβ protein, such as Alzheimer's Disease.

Cellular screening methods for inhibitors of Aβ production, testing methods for the in vivo suppression of Aβ production, and assays for the detection of secretase activity are known in the art and have been disclosed in numerous publications, including PCT publication number WO 98/22493, EPO publication number 0652009, U.S. Pat. No. 5,703,129 and U.S. Pat. No. 5,593,846; all hereby incorporated by reference.

The compounds of the present invention have utility for the prevention and treatment of disorders involving Aβ production, such as cerebrovascular disorders.

Compounds of the present invention have been shown to inhibit Aβ production, as determined by the secretase inhibition assay described below.

Compounds of the present invention have been shown to inhibit Aβ production, utilizing the C-terminus b amyloid precursor protein accumulation assay described below.

Compounds of Formula (I) are expected to possess γ-secretase inhibitory activity. The γ-secretase inhibitory activity of the compounds of the present invention is demonstrated using assays for such activity, for Example, using the assay described below. Compounds of the present invention have been shown to inhibit the activity of γ-secretase, as determined by the Aβ immunoprecipitation assay.

Compounds provided by this invention should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit Aβ production. These would be provided in commercial kits comprising a compound of this invention.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L” denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar, “nm” denotes nanometer, “SDS” denotes sodium dodecyl sulfate, and “DMSO” denotes dimethyl sulfoxide, and “EDTA” denotes ethylenediaminetetraacetato.

A compound is considered to be active if it has an IC₅₀ or K_(i) value of less than about 100 μM for the inhibition of Aβ production or inhibition of proteolytic activity leading to Aβ production. Compounds, as demonstrated by use of the invention, have demonstrated IC₅₀ values, for the inhibition of Aβ production, of less than about 100 μM. Preferably compounds, as demonstrated by use of the invention, demonstrate IC₅₀ values, for the inhibition of Aβ production, of less than about 1 μM. More preferably compounds, as demonstrated by use of the invention, demonstrate IC₅₀ values, for the inhibition of Aβ production, of less than about 100 nM. Even more preferably compounds, as demonstrated by use of the invention, demonstrate IC₅₀ values, for the inhibition of Aβ production, of less than about 50 nM.

β Amyloid Precursor Protein Accumulation Assay (βAPPA Assay)

An assay to evaluate the accumulation of Aβ protein was developed to detect potential inhibitors of secretases. The assay uses the N 9 cell line, characterized for expression of exogenous APP by immunoblotting and immunoprecipitation.

The effect of test compounds on the accumulation of Aβ in the conditioned medium is tested by immunoprecipitation. N 9 cells are grown to confluency in 6-well plates and washed twice with 1×Hank's buffered salt solution. The cells are starved in methionine/cysteine deficient media for 30 min., followed by replacement with fresh deficient media containing 150 uCi Tran35S-LABEL™ (ICN). Test compounds dissolved in DMSO (final concentration 1%) are added, over a range of 1 picomolar to 100 micromolar, together with the addition of the fresh media containing Tran35S-LABEL™. The cells are incubated for 4 h at 37° C. in a tissue culture incubator.

At the end of the incubation period, the conditioned medium is harvested and pre-cleared by the addition of 5 μl normal mouse serum and 50 ul of protein A Sepharose (Pharmacia), mixed by end-over-end rotation for 30 minutes at 4° C., followed by a brief centrifugation in a microfuge. The supernatant is then harvested and transferred to fresh tubes containing 5 ug of a monoclonal antibody (examples of antibodies include but are not limited by, clone 1101.1, directed against an internal peptide sequence in Aβ; or 6E10 from Senetek; or 4G8 from Senetek; additionally polyclonals from rabbit antihuman Aβ from Boehringer Mannheim) and 50 μl protein A Sepharose. After incubation overnight at 4° C., the samples are washed three times with high salt washing buffer (50 mM Tris, pH 7.5, 500 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), three times with low salt wash buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), and three times with 10 mM Tris, pH 7.5. The pellet after the last wash is resuspended in SDS sample buffer (Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriphage T4. Nature 227, 680-5, 1970.) and boiled for 3 minutes. The supernatant is then fractionated on either 10-20% Tris/Tricine SDS gels or on 16.5% Tris/Tricine SDS gels. The gels are dried and exposed to X-ray film or analyzed by phosphorimaging. The resulting image is analyzed for the presence of Aβ polypeptides. The steady-state level of Aβ in the presence of a test compound is compared to wells treated with DMSO (1%) alone. A typical test compound in this assay blocks Aβ accumulation in the conditioned medium, and is considered active with an IC₅₀ less than 100 μM.

C-Terminus β-Amyloid Precursor Protein Accumulation Assay (CTF Assay)

The effect of test compounds on the accumulation of C-terminal fragments is determined by immunoprecipitation of APP and fragments thereof from cell lysates. N 9 cells are metabolically labeled, as above, with media containing Tran35S-LABEL™, in the presence or absence of test compounds. At the end of the incubation period, the conditioned medium are harvested and cells lysed in RIPA buffer (10 mM Tris, pH 8.0 containing 1% Triton X-100, 1% deoxycholate, 0.1% SDS, 150 mM NaCl, 0.125% NaN₃). Again, lysates are precleared with 5 ul normal rabbit serum/50 ul protein A Sepharose, followed by the addition of BC-1 antiserum (15 μl;) and 50 μl protein A Sepharose for 16 hours at 4° C. The immunoprecipitates are washed as above, bound proteins eluted by boiling in SDS sample buffer and fractionated by Tris/Tricine SDS-PAGE. After exposure to X-ray film or phosphorimager, the resulting images are analyzed for the presence of C-terminal APP fragments. The steady-state level of C-terminal APP fragments is compared to wells treated with DMSO (1%) alone. A typical test compound in this assay stimulates C-terminal fragment accumulation in the cell lysates, and is considered active with an IC₅₀ less than 100 μM.

Accumulation-Release Assay

This immunoprecipitation assay is specific for g secretase activity (i.e., proteolytic activity required to generate the C-terminal end of Aβ either by direct cleavage or generating a C-terminal extended species which is subsequently further proteolyzed). N 9 cells are pulse labeled with media containing Tran35S-LABEL™ in the presence of a reported 9 secretase inhibitor (MDL 28170; Higaki J, Quon D, Zhong Z, Cordell B. Inhibition of beta-amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 14, 651-659, 1995) for 1 h, followed by washing to remove ³⁵S radiolabel and MDL 28170. The media is replaced and test compounds are added over a dose range (for example 0.1 nM to 100 uM). The cells are chased for increasing periods of times and Aβ is isolated from the conditioned medium and C-terminal fragments from cell lysates (see accumulation assay above). The activity of test compounds are characterized by whether a stabilization of C-terminal fragments is observed and whether Aβ is generated from these accumulated precursor. A typical test compound in this assay prevents the generation of Aβ out of accumulated C-terminal fragments and is considered active with an IC₅₀ less than 100 μM.

Dosage and Formulation

The compounds determined from the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration. The active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions. The active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier. A valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.

The compounds determined from the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed to prevent or treat neurological disorders related to β-amyloid production or accumulation, such as Alzheimer's disease and Down's Syndrome.

The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a host, such as a human or a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds determined from the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

Advantageously, compounds determined from the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

The compounds identified using the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds determined from the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds determined from the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

The Tables below provide representative Examples of the compounds of Formula (I) of the present invention.

TABLE 1

Ex # R¹ R² R³ Z—Y—X—W  1 H OH propyl 3,3-diphenylpropyl  2 H OH propyl 3-phenoxybenzyl  3 H OH propyl phenyl  4 H CH₃ propyl 3-phenoxybenzyl  5 CH₃ OCH₃ propyl 3phenoxybenzyl  6 H OCH₃ propyl 3-phenoxybenzyl  7 H H propyl 3-phenoxybenzyl  7A H NH₂ propyl 3-phenoxybenzyl  8 H H allyl 3-phenoxybenzyl  9 H OH allyl 3-phenoxybenzyl 10 H OH propyl 3-(2,4-dichlorophenyl)- benzyl 11 H OH propyl 3-(4-fluorophenyl)-benzyl 12 H OH propyl 3-(4-methylphenyl)-benzyl 13 H OH propyl 3-(4-methoxyphenyl)-benzyl 14 H OH propyl 3-(3-methylphenyl)-benzyl 15 H OH propyl 3-(3-chloro-4- fluorophenyl)-benzyl 16 H OH propyl 3-(4-trifluoromethyl- phenyl)benzyl 17 H OH propyl 3-(3-methoxyphenyl)-benzyl 18 H OH propyl 3-(3-fluorophenyl)-benzyl 19 H OH propyl 3-(2-methoxyphenyl)-benzyl 20 H OH propyl 3-(2-naphthyl)benzyl 21 H H propyl 3-(4-methoxyphenyl)-benzyl 22 H H propyl 3-(3-fluorophenyl)-benzyl 23 H H propyl 3-(4-F₃C-phenyl)benzyl 24 H H propyl 3-(2,4-Cl₂-phenyl)benzyl 25 H H propyl 3-(4-H₃C-phenyl)benzyl 26 H H propyl 3-(4-H₃CO-phenyl)benzyl 27 H H propyl 3-(3-Cl,4-F-phenyl)-benzyl 28 H H propyl 3-(3-H₃CO-phenyl)benzyl 29 H H propyl 3-(2-H₃CO-phenyl)benzyl 30 H H propyl 3-(4-H₃CO-phenyl)-pyrid-5- ylmethyl 31 H H propyl 3-(4-F₃C-phenyl)-pyrid-5- ylmethyl 32 H H propyl 3-(3-Cl,4-F-phenyl)-pyrid- 5-ylmethyl 33 H n-butyl propyl 3-phenoxybenzyl 34 H 2- propyl 3-phenoxybenzyl furyl- methyl 35 H C₅H₉ propyl 3-phenoxybenzyl 36 H cinnamyl propyl 3-phenoxybenzyl 37 H H allyl benzophenone-3-yl-methyl 38 H H propyl benzophenone-3-yl-methyl 39 H H propyl 4-(4-F₃C-phenyl)benzyl 40* H H i-butyl 3-(2-tetrazolyl-phenyl)- R⁵ = propyl benzyl 41* H H i-butyl 3-phenoxybenzyl R⁵ = propyl 43 H H H 3-phenoxybenzyl *For these compounds the i-butyl substituent on the carbon adjacent to CR³ in the captioned figure is actually n-propyl.

Table 2 demonstrates representative compounds envisaged within the scope of the present invention. Each formulae at the start of Table 2 are intended to be paired with each entry in the table which follows.

For example the compound (2R,3S) N1-[(3S)-hexahydro-1-(3-(3,4-dimethoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide is represented by Example #139-A-j, which comprises the core A, succinate j, and entry #139.

For example the compound (2R,3S) N1-[6,7-dihydro-5-(3-(3,4-dimethoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide is represented by Example #139-B-j, which comprises the core B, succinate j, and entry #139.

For example the compound (2R,3S) N1-[1,3,4,5-tetrahydro-1-(3,4-dimethoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide, is represented by Example #139-C-ab, which comprises the core C, succinate ab, and entry #139.

TABLE 2

A

B

C

D

E

F

G

H

J

K wherein R³ and R⁵ are:

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

ab

ac

ad

ae

af

ag

ah

ai

aj

ak

al

am

an

ao

ap

aq

ar

as

at

au

av

aw

ax

ay

az

ba

bb

bc

bd

be

bf

bg

bh

bi

bj

bk

bl

bm

bn

bo

bp

bq

br

bs

bt Ex. # W X Y Z  100 —CH₂— phen-1,3-diyl bond phenyl  101 —CH₂— phen-1,3-diyl bond 3,3- diphenylmethyl  102 —CH₂— phen-1,3-diyl bond 2-F-phenyl  103 —CH₂— phen-1,3-diyl bond 3-F-phenyl  104 —CH₂— phen-1,3-diyl bond 4-F-phenyl  105 —CH₂— phen-1,3-diyl bond 2-Cl-phenyl  106 —CH₂— phen-1,3-diyl bond 3-Cl-phenyl  107 —CH₂— phen-1,3-diyl bond 4-Cl-phenyl  108 —CH₂— phen-1,3-diyl bond 2-Me-phenyl  109 —CH₂— phen-1,3-diyl bond 3-Me-phenyl  110 —CH₂— phen-1,3-diyl bond 4-Me-phenyl  111 —CH₂— phen-1,3-diyl bond 2-MeO-phenyl  112 —CH₂— phen-1,3-diyl bond 3-MeO-phenyl  113 —CH₂— phen-1,3-diyl bond 4-MeO-phenyl  114 —CH₂— phen-1,3-diyl bond 2-MeS-phenyl  115 —CH₂— phen-1,3-diyl bond 3-MeS-phenyl  116 —CH₂— phen-1,3-diyl bond 4-MeS-phenyl  117 —CH₂— phen-1,3-diyl bond 2-F₃C-phenyl  118 —CH₂— phen-1,3-diyl bond 3-F₃C-phenyl  119 —CH₂— phen-1,3-diyl bond 4-F₃C-phenyl  120 —CH₂— phen-1,3-diyl bond 2,3-diF-phenyl  121 —CH₂— phen-1,3-diyl bond 2,4-diF-phenyl  122 —CH₂— phen-1,3-diyl bond 2,5-diF-phenyl  123 —CH₂— phen-1,3-diyl bond 2,6-diF-phenyl  124 —CH₂— phen-1,3-diyl bond 3,4-diF-phenyl  125 —CH₂— phen-1,3-diyl bond 3,5-diF-phenyl  126 —CH₂— phen-1,3-diyl bond 2,3-diCl-phenyl  127 —CH₂— phen-1,3-diyl bond 2,4-diCl-phenyl  128 —CH₂— phen-1,3-diyl bond 2,5-diCl-phenyl  129 —CH₂— phen-1,3-diyl bond 2,6-diCl-phenyl  130 —CH₂— phen-1,3-diyl bond 3,4-diCl-phenyl  131 —CH₂— phen-1,3-diyl bond 3,5-diCl-phenyl  132 —CH₂— phen-1,3-diyl bond 2-Cl-3-F-phenyl  133 —CH₂— phen-1,3-diyl bond 2-Cl-4-F-phenyl  134 —CH₂— phen-1,3-diyl bond 2-Cl-5-F-phenyl  135 —CH₂— phen-1,3-diyl bond 3-Cl-4-P-phenyl  136 —CH₂— phen-1,3-diyl bond 3-Cl-5-F-phenyl  137 —CH₂— phen-1,3-diyl bond 4-Cl-2-F-phenyl  138 —CH₂— phen-1,3-diyl bond 4-Cl-3-F-phenyl  139 —CH₂— phen-1,3-diyl bond 2,3-diMeO- phenyl  140 —CH₂— phen-1,3-diyl bond 2,4-diMeO- phenyl  141 —CH₂— phen-1,3-diyl bond 2,5-diMeO- phenyl  142 —CH₂— phen-1,3-diyl bond 2,6-diMeO- phenyl  143 —CH₂— phen-1,3-diyl bond 3,4-diMeO- phenyl  144 —CH₂— phen-1,3-diyl bond 3,5-diMeO- phenyl  145 —CH₂— phen-1,3-diyl bond cyclopropyl  146 —CH₂— phen-1,3-diyl bond cyclobutyl  147 —CH₂— phen-1,3-diyl bond cyclopentyl  148 —CH₂— phen-1,3-diyl bond cyclohexyl  149 —CH₂— phen-1,3-diyl bond 2-furanyl  150 —CH₂— phen-1,3-diyl bond 2-thienyl  151 —CH₂— phen-1,3-diyl bond 2-imidazolyl  152 —CH₂— phen-1,3-diyl bond 2-pyridyl  153 —CH₂— phen-1,3-diyl bond 3-pyridyl  154 —CH₂— phen-1,3-diyl bond 4-pyridyl  155 —CH₂— phen-1,3-diyl bond N-morpholinyl  156 —CH₂— phen-1,3-diyl bond N-piperidinyl  157 —CH₂— phen-1,3-diyl bond 3-Me-2-pyridyl  158 —CH₂— phen-1,3-diyl bond 4-Me-2-pyridyl  159 —CH₂— phen-1,3-diyl bond 1-indolyl  160 —CH₂— phen-1,3-diyl bond 2-benzothienyl  161 —CH₂— phen-1,3-diyl bond 2-benzofuranyl  162 —CH₂— phen-1,3-diyl bond 1-benzimidazole  163 —CH₂— phen-1,3-diyl bond 2-naphthyl  164 —CH₂— pyridin-3,5-diyl bond phenyl  165 —CH₂— pyridin-3,5-diyl bond 3,3- diphenylmethyl  166 —CH₂— pyridin-3,5-diyl bond 2-F-phenyl  167 —CH₂— pyridin-3,5-diyl bond 3-F-phenyl  168 —CH₂— pyridin-3,5-diyl bond 4-F-phenyl  169 —CH₂— pyridin-3,5-diyl bond 2-Cl-phenyl  170 —CH₂— pyridin-3,5-diyl bond 3-Cl-phenyl  171 —CH₂— pyridin-3,5-diyl bond 4-Cl-phenyl  172 —CH₂— pyridin-3,5-diyl bond 2-Me-phenyl  173 —CH₂— pyridin-3,5-diyl bond 3-Me-phenyl  174 —CH₂— pyridin-3,5-diyl bond 4-Me-phenyl  175 —CH₂— pyridin-3,5-diyl bond 2-MeO-phenyl  176 —CH₂— pyridin-3,5-diyl bond 3-MeO-phenyl  177 —CH₂— pyridin-3,5-diyl bond 4-MeO-phenyl  178 —CH₂— pyridin-3,5-diyl bond 2-MeS-phenyl  179 —CH₂— pyridin-3,5-diyl bond 3-MeS-phenyl  180 —CH₂— pyridin-3,5-diyl bond 4-MeS-phenyl  181 —CH₂— pyridin-3,5-diyl bond 2-F₃C-phenyl  182 —CH₂— pyridin-3,5-diyl bond 3-F₃C-phenyl  183 —CH₂— pyridin-3,5-diyl bond 4-F₃C-phenyl  184 —CH₂— pyridin-3,5-diyl bond 2,3-diF-phenyl  185 —CH₂— pyridin-3,5-diyl bond 2,4-diF-phenyl  186 —CH₂— pyridin-3,5-diyl bond 2,5-diF-phenyl  187 —CH₂— pyridin-3,5-diyl bond 2,6-diF-phenyl  188 —CH₂— pyridin-3,5-diyl bond 3,4-diF-phenyl  189 —CH₂— pyridin-3,5-diyl bond 3,5-diF-phenyl  190 —CH₂— pyridin-3,5-diyl bond 2,3-diCl-phenyl  191 —CH₂— pyridin-3,5-diyl bond 2,4-diCl-phenyl  192 —CH₂— pyridin-3,5-diyl bond 2,5-diCl-phenyl  193 —CH₂— pyridin-3,5-diyl bond 2,6-diCl-phenyl  194 —CH₂— pyridin-3,5-diyl bond 3,4-diCl-phenyl  195 —CH₂— pyridin-3,5-diyl bond 3,5-diCl-phenyl  196 —CH₂— pyridin-3,5-diyl bond 2-Cl-3-F-phenyl  197 —CH₂— pyridin-3,5-diyl bond 2-Cl-4-F-phenyl  198 —CH₂— pyridin-3,5-diyl bond 2-Cl-5-F-phenyl  199 —CH₂— pyridin-3,5-diyl bond 3-Cl-4-F-phenyl  200 —CH₂— pyridin-3,5-diyl bond 3-Cl-5-F-phenyl  201 —CH₂— pyridin-3,5-diyl bond 4-Cl-2-F-phenyl  202 —CH₂— pyridin-3,5-diyl bond 4-Cl-3-F-phenyl  203 —CH₂— pyridin-3,5-diyl bond 2,3-diMeO- phenyl  204 —CH₂— pyridin-3,5-diyl bond 2,4-diMeO- phenyl  205 —CH₂— pyridin-3,5-diyl bond 2,5-diMeO- phenyl  206 —CH₂— pyridin-3,5-diyl bond 2,6-diMeO- phenyl  207 —CH₂— pyridin-3,5-diyl bond 3,4-diMeO- phenyl  208 —CH₂— pyridin-3,5-diyl bond 3,5-diMeO- phenyl  209 —CH₂— pyridin-3,5-diyl bond cyclopropyl  210 —CH₂— pyridin-3,5-diyl bond cyclobutyl  211 —CH₂— pyridin-3,5-diyl bond cyclopentyl  212 —CH₂— pyridin-3,5-diyl bond cyclohexyl  213 —CH₂— pyridin-3,5-diyl bond 2-furanyl  214 —CH₂— pyridin-3,5-diyl bond 2-thienyl  215 —CH₂— pyridin-3,5-diyl bond 2-imidazolyl  216 —CH₂— pyridin-3,5-diyl bond 2-pyridyl  217 —CH₂— pyridin-3,5-diyl bond 3-pyridyl  218 —CH₂— pyridin-3,5-diyl bond 4-pyridyl  219 —CH₂— pyridin-3,5-diyl bond N-morpholinyl  220 —CH₂— pyridin-3,5-diyl bond N-piperidinyl  221 —CH₂— pyridin-3,5-diyl bond 3-Me-2-pyridyl  222 —CH₂— pyridin-3,5-diyl bond 4-Me-2-pyridyl  223 —CH₂— pyridin-3,5-diyl bond 1-indolyl  224 —CH₂— pyridin-3,5-diyl bond 2-benzothienyl  225 —CH₂— pyridin-3,5-diyl bond 2-benzofuranyl  226 —CH₂— pyridin-3,5-diyl bond 1-benzimidazole  227 —CH₂— pyridin-3,5-diyl bond 2-naphthyl  228 —CH₂— pyridin-2,6-diyl bond phenyl  229 —CH₂— pyridin-2,6-diyl bond 3,3- diphenylmethyl  230 —CH₂— pyridin-2,6-diyl bond 2-F-phenyl  231 —CH₂— pyridin-2,6-diyl bond 3-F-phenyl  232 —CH₂— pyridin-2,6-diyl bond 4-F-phenyl  233 —CH₂— pyridin-2,6-diyl bond 2-Cl-phenyl  234 —CH₂— pyridin-2,6-diyl bond 3-Cl-phenyl  235 —CH₂— pyridin-2,6-diyl bond 4-Cl-phenyl  236 —CH₂— pyridin-2,6-diyl bond 2-Me-phenyl  237 —CH₂— pyridin-2,6-diyl bond 3-Me-phenyl  238 —CH₂— pyridin-2,6-diyl bond 4-Me-phenyl  239 —CH₂— pyridin-2,6-diyl bond 2-MeO-phenyl  240 —CH₂— pyridin-2,6-diyl bond 3-MeO-phenyl  241 —CH₂— pyridin-2,6-diyl bond 4-MeO-phenyl  242 —CH₂— pyridin-2,6-diyl bond 2-MeS-phenyl  243 —CH₂— pyridin-2,6-diyl bond 3-MeS-phenyl  244 —CH₂— pyridin-2,6-diyl bond 4-MeS-phenyl  245 —CH₂— pyridin-2,6-diyl bond 2-F₃C-phenyl  246 —CH₂— pyridin-2,6-diyl bond 3-F₃C-phenyl  247 —CH₂— pyridin-2,6-diyl bond 4-F₃C-phenyl  248 —CH₂— pyridin-2,6-diyl bond 2,3-diF-phenyl  249 —CH₂— pyridin-2,6-diyl bond 2,4-diF-phenyl  250 —CH₂— pyridin-2,6-diyl bond 2,5-diF-phenyl  251 —CH₂— pyridin-2,6-diyl bond 2,6-diF-phenyl  252 —CH₂— pyridin-2,6-diyl bond 3,4-diF-phenyl  253 —CH₂— pyridin-2,6-diyl bond 3,5-diF-phenyl  254 —CH₂— pyridin-2,6-diyl bond 2,3-diCl-phenyl  255 —CH₂— pyridin-2,6-diyl bond 2,4-diCl-phenyl  256 —CH₂— pyridin-2,6-diyl bond 2,5-diCl-phenyl  257 —CH₂— pyridin-2,6-diyl bond 2,6-diCl-phenyl  258 —CH₂— pyridin-2,6-diyl bond 3,4-diCl-phenyl  259 —CH₂— pyridin-2,6-diyl bond 3,5-diCl-phenyl  260 —CH₂— pyridin-2,6-diyl bond 2-Cl-3-F-phenyl  261 —CH₂— pyridin-2,6-diyl bond 2-Cl-4-F-phenyl  262 —CH₂— pyridin-2,6-diyl bond 2-Cl-5-F-phenyl  263 —CH₂— pyridin-2,6-diyl bond 3-Cl-4-F-phenyl  264 —CH₂— pyridin-2,6-diyl bond 3-Cl-5-F-phenyl  265 —CH₂— pyridin-2,6-diyl bond 4-Cl-2-F-phenyl  266 —CH₂— pyridin-2,6-diyl bond 4-Cl-3-F-phenyl  267 —CH₂— pyridin-2,6-diyl bond 2,3-diMeO- phenyl  268 —CH₂— pyridin-2,6-diyl bond 2,4-diMeO- phenyl  269 —CH₂— pyridin-2,6-diyl bond 2,5-diMeO- phenyl  270 —CH₂— pyridin-2,6-diyl bond 2,6-diMeO- phenyl  271 —CH₂— pyridin-2,6-diyl bond 3,4-diMeO- phenyl  272 —CH₂— pyridin-2,6-diyl bond 3,5-diMeO- phenyl  273 —CH₂— pyridin-2,6-diyl bond cyclopropyl  274 —CH₂— pyridin-2,6-diyl bond cyclobutyl  275 —CH₂— pyridin-2,6-diyl bond cyclopentyl  276 —CH₂— pyridin-2,6-diyl bond cyclohexyl  277 —CH₂— pyridin-2,6-diyl bond 2-furanyl  278 —CH₂— pyridin-2,6-diyl bond 2-thienyl  279 —CH₂— pyridin-2,6-diyl bond 2-imidazolyl  280 —CH₂— pyridin-2,6-diyl bond 2-pyridyl  281 —CH₂— pyridin-2,6-diyl bond 3-pyridyl  282 —CH₂— pyridin-2,6-diyl bond 4-pyridyl  283 —CH₂— pyridin-2,6-diyl bond N-morpholinyl  284 —CH₂— pyridin-2,6-diyl bond N-piperidinyl  285 —CH₂— pyridin-2,6-diyl bond 3-Me-2-pyridyl  286 —CH₂— pyridin-2,6-diyl bond 4-Me-2-pyridyl  287 —CH₂— pyridin-2,6-diyl bond 1-indolyl  288 —CH₂— pyridin-2,6-diyl bond 2-benzothienyl  289 —CH₂— pyridin-2,6-diyl bond 2-benzofuranyl  290 —CH₂— pyridin-2,6-diyl bond 1-benzimidazole  291 —CH₂— pyridin-2,6-diyl bond 2-naphthyl  292 —CH₂— pyridin-2,4-diyl bond phenyl  293 —CH₂— pyridin-2,4-diyl bond 3,3- diphenylmethyl  294 —CH₂— pyridin-2,4-diyl bond 2-F-phenyl  295 —CH₂— pyridin-2,4-diyl bond 3-F-phenyl  296 —CH₂— pyridin-2,4-diyl bond 4-F-phenyl  297 —CH₂— pyridin-2,4-diyl bond 2-Cl-phenyl  298 —CH₂— pyridin-2,4-diyl bond 3-Cl-phenyl  299 —CH₂— pyridin-2,4-diyl bond 4-Cl-phenyl  300 —CH₂— pyridin-2,4-diyl bond 2-Me-phenyl  301 —CH₂— pyridin-2,4-diyl bond 3-Me-phenyl  302 —CH₂— pyridin-2,4-diyl bond 4-Me-phenyl  303 —CH₂— pyridin-2,4-diyl bond 2-MeO-phenyl  304 —CH₂— pyridin-2,4-diyl bond 3-MeO-phenyl  305 —CH₂— pyridin-2,4-diyl bond 4-MeO-phenyl  306 —CH₂— pyridin-2,4-diyl bond 2-MeS-phenyl  307 —CH₂— pyridin-2,4-diyl bond 3-MeS-phenyl  308 —CH₂— pyridin-2,4-diyl bond 4-MeS-phenyl  309 —CH₂— pyridin-2,4-diyl bond 2-F₃C-phenyl  310 —CH₂— pyridin-2,4-diyl bond 3-F₃C-phenyl  311 —CH₂— pyridin-2,4-diyl bond 4-F₃C-phenyl  312 —CH₂— pyridin-2,4-diyl bond 2,3-diF-phenyl  313 —CH₂— pyridin-2,4-diyl bond 2,4-diF-phenyl  314 —CH₂— pyridin-2,4-diyl bond 2,5-diF-phenyl  315 —CH₂— pyridin-2,4-diyl bond 2,6-diF-phenyl  316 —CH₂— pyridin-2,4-diyl bond 3,4-diF-phenyl  317 —CH₂— pyridin-2,4-diyl bond 3,5-diF-phenyl  318 —CH₂— pyridin-2,4-diyl bond 2,3-diCl-phenyl  319 —CH₂— pyridin-2,4-diyl bond 2,4-diCl-phenyl  320 —CH₂— pyridin-2,4-diyl bond 2,5-diCl-phenyl  321 —CH₂— pyridin-2,4-diyl bond 2,6-diCl-phenyl  322 —CH₂— pyridin-2,4-diyl bond 3,4-diCl-phenyl  323 —CH₂— pyridin-2,4-diyl bond 3,5-diCl-phenyl  324 —CH₂— pyridin-2,4-diyl bond 2-Cl-3-F-phenyl  325 —CH₂— pyridin-2,4-diyl bond 2-Cl-4-F-phenyl  326 —CH₂— pyridin-2,4-diyl bond 2-Cl-5-F-phenyl  327 —CH₂— pyridin-2,4-diyl bond 3-Cl-4-F-phenyl  328 —CH₂— pyridin-2,4-diyl bond 3-Cl-5-F-phenyl  329 —CH₂— pyridin-2,4-diyl bond 4-Cl-2-F-phenyl  330 —CH₂— pyridin-2,4-diyl bond 4-Cl-3-F-phenyl  331 —CH₂— pyridin-2,4-diyl bond 2,3-diMeO- phenyl  332 —CH₂— pyridin-2,4-diyl bond 2,4-diMeO- phenyl  333 —CH₂— pyridin-2,4-diyl bond 2,5-diMeO- phenyl  334 —CH₂— pyridin-2,4-diyl bond 2,6-diMeO- phenyl  335 —CH₂— pyridin-2,4-diyl bond 3,4-diMeO- phenyl  336 —CH₂— pyridin-2,4-diyl bond 3,5-diMeO- phenyl  337 —CH₂— pyridin-2,4-diyl bond cyclopropyl  338 —CH₂— pyridin-2,4-diyl bond cyclobutyl  339 —CH₂— pyridin-2,4-diyl bond cyclopentyl  340 —CH₂— pyridin-2,4-diyl bond cyclohexyl  341 —CH₂— pyridin-2,4-diyl bond 2-furanyl  342 —CH₂— pyridin-2,4-diyl bond 2-thienyl  343 —CH₂— pyridin-2,4-diyl bond 2-imidazolyl  344 —CH₂— pyridin-2,4-diyl bond 2-pyridyl  345 —CH₂— pyridin-2,4-diyl bond 3-pyridyl  346 —CH₂— pyridin-2,4-diyl bond 4-pyridyl  347 —CH₂— pyridin-2,4-diyl bond N-morpholinyl  348 —CH₂— pyridin-2,4-diyl bond N-piperidinyl  349 —CH₂— pyridin-2,4-diyl bond 3-Me-2-pyridyl  350 —CH₂— pyridin-2,4-diyl bond 4-Me-2-pyridyl  351 —CH₂— pyridin-2,4-diyl bond 1-indolyl  352 —CH₂— pyridin-2,4-diyl bond 2-benzothienyl  353 —CH₂— pyridin-2,4-diyl bond 2-benzofuranyl  354 —CH₂— pyridin-2,4-diyl bond 1-benzimidazole  355 —CH₂— pyridin-2,4-diyl bond 2-naphthyl  356 —CH₂— pyridin-4,2-diyl bond phenyl  357 —CH₂— pyridin-4,2-diyl bond 3,3- diphenylmethyl  358 —CH₂— pyridin-4,2-diyl bond 2-F-phenyl  359 —CH₂— pyridin-4,2-diyl bond 3-F-phenyl  360 —CH₂— pyridin-4,2-diyl bond 4-F-phenyl  361 —CH₂— pyridin-4,2-diyl bond 2-Cl-phenyl  362 —CH₂— pyridin-4,2-diyl bond 3-Cl-phenyl  363 —CH₂— pyridin-4,2-diyl bond 4-Cl-phenyl  364 —CH₂— pyridin-4,2-diyl bond 2-Me-phenyl  365 —CH₂— pyridin-4,2-diyl bond 3-Me-phenyl  366 —CH₂— pyridin-4,2-diyl bond 4-Me-phenyl  367 —CH₂— pyridin-4,2-diyl bond 2-MeO-phenyl  368 —CH₂— pyridin-4,2-diyl bond 3-MeO-phenyl  369 —CH₂— pyridin-4,2-diyl bond 4-MeO-phenyl  370 —CH₂— pyridin-4,2-diyl bond 2-MeS-phenyl  371 —CH₂— pyridin-4,2-diyl bond 3-MeS-phenyl  372 —CH₂— pyridin-4,2-diyl bond 4-MeS-phenyl  373 —CH₂— pyridin-4,2-diyl bond 2-F₃C-phenyl  374 —CH₂— pyridin-4,2-diyl bond 3-F₃C-phenyl  375 —CH₂— pyridin-4,2-diyl bond 4-F₃C-phenyl  376 —CH₂— pyridin-4,2-diyl bond 2,3-diF-phenyl  377 —CH₂— pyridin-4,2-diyl bond 2,4-diF-phenyl  378 —CH₂— pyridin-4,2-diyl bond 2,5-diF-phenyl  379 —CH₂— pyridin-4,2-diyl bond 2,6-diF-phenyl  380 —CH₂— pyridin-4,2-diyl bond 3,4-diF-phenyl  381 —CH₂— pyridin-4,2-diyl bond 3,5-diF-phenyl  382 —CH₂— pyridin-4,2-diyl bond 2,3-diCl-phenyl  383 —CH₂— pyridin-4,2-diyl bond 2,4-diCl-phenyl  384 —CH₂— pyridin-4,2-diyl bond 2,5-diCl-phenyl  385 —CH₂— pyridin-4,2-diyl bond 2,6-diCl-phenyl  386 —CH₂— pyridin-4,2-diyl bond 3,4-diCl-phenyl  387 —CH₂— pyridin-4,2-diyl bond 3,5-diCl-phenyl  388 —CH₂— pyridin-4,2-diyl bond 2-Cl-3-F-phenyl  389 —CH₂— pyridin-4,2-diyl bond 2-Cl-4-F-phenyl  390 —CH₂— pyridin-4,2-diyl bond 2-Cl-5-F-phenyl  391 —CH₂— pyridin-4,2-diyl bond 3-Cl-4-F-phenyl  392 —CH₂— pyridin-4,2-diyl bond 3-Cl-5-F-phenyl  393 —CH₂— pyridin-4,2-diyl bond 4-Cl-2-F-phenyl  394 —CH₂— pyridin-4,2-diyl bond 4-Cl-3-F-phenyl  395 —CH₂— pyridin-4,2-diyl bond 2,3-diMeO- phenyl  396 —CH₂— pyridin-4,2-diyl bond 2,4-diMeO- phenyl  397 —CH₂— pyridin-4,2-diyl bond 2,5-diMeO- phenyl  398 —CH₂— pyridin-4,2-diyl bond 2,6-diMeO- phenyl  399 —CH₂— pyridin-4,2-diyl bond 3,4-diMeO- phenyl  400 —CH₂— pyridin-4,2-diyl bond 3,5-diMeO- phenyl  401 —CH₂— pyridin-4,2-diyl bond cyclopropyl  402 —CH₂— pyridin-4,2-diyl bond cyclobutyl  403 —CH₂— pyridin-4,2-diyl bond cyclopentyl  404 —CH₂— pyridin-4,2-diyl bond cyclohexyl  405 —CH₂— pyridin-4,2-diyl bond 2-furanyl  406 —CH₂— pyridin-4,2-diyl bond 2-thienyl  407 —CH₂— pyridin-4,2-diyl bond 2-imidazolyl  408 —CH₂— pyridin-4,2-diyl bond 2-pyridyl  409 —CH₂— pyridin-4,2-diyl bond 3-pyridyl  410 —CH₂— pyridin-4,2-diyl bond 4-pyridyl  411 —CH₂— pyridin-4,2-diyl bond N-morpholinyl  412 —CH₂— pyridin-4,2-diyl bond N-piperidinyl  413 —CH₂— pyridin-4,2-diyl bond 3-Me-2-pyridyl  414 —CH₂— pyridin-4,2-diyl bond 4-Me-2-pyridyl  415 —CH₂— pyridin-4,2-diyl bond 1-indolyl  416 —CH₂— pyridin-4,2-diyl bond 2-benzothienyl  417 —CH₂— pyridin-4,2-diyl bond 2-benzofuranyl  418 —CH₂— pyridin-4,2-diyl bond 1-benzimidazole  419 —CH₂— pyridin-4,2-diyl bond 2-naphthyl  420 —CH₂— piperidin-1,3- bond phenyl diyl  421 —CH₂— piperidin-1,3- bond 3,3- diyl diphenylmethyl  422 —CH₂— piperidin-1,3- bond 2-F-phenyl diyl  423 —CH₂— piperidin-1,3- bond 3-F-phenyl diyl  424 —CH₂— piperidin-1,3- bond 4-F-phenyl diyl  425 —CH₂— piperidin-1,3- bond 2-Cl-phenyl diyl  426 —CH₂— piperidin-1,3- bond 3-Cl-phenyl diyl  427 —CH₂— piperidin-1,3- bond 4-Cl-phenyl diyl  428 —CH₂— piperidin-1,3- bond 2-Me-phenyl diyl  429 —CH₂— piperidin-1,3- bond 3-Me-phenyl diyl  430 —CH₂— piperidin-1,3- bond 4-Me-phenyl diyl  431 —CH₂— piperidin-1,3- bond 2-MeO-phenyl diyl  432 —CH₂— piperidin-1,3- bond 3-MeO-phenyl diyl  433 —CH₂— piperidin-1,3- bond 4-MeO-phenyl diyl  434 —CH₂— piperidin-1,3- bond 2-MeS-phenyl diyl  435 —CH₂— piperidin-1,3- bond 3-MeS-phenyl diyl  436 —CH₂— piperidin-1,3- bond 4-MeS-phenyl diyl  437 —CH₂— piperidin-1,3- bond 2-F₃C-phenyl diyl  438 —CH₂— piperidin-1,3- bond 3-F₃C-phenyl diyl  439 —CH₂— piperidin-1,3- bond 4-F₃C-phenyl diyl  440 —CH₂— piperidin-1,3- bond 2,3-diF-phenyl diyl  441 —CH₂— piperidin-1,3- bond 2,4-diF-phenyl diyl  442 —CH₂— piperidin-1,3- bond 2,5-diF-phenyl diyl  443 —CH₂— piperidin-1,3- bond 2,6-diF-phenyl diyl  444 —CH₂— piperidin-1,3- bond 3,4-diF-phenyl diyl  445 —CH₂— piperidin-1,3- bond 3,5-diF-phenyl diyl  446 —CH₂— piperidin-1,3- bond 2,3-diCl-phenyl diyl  447 —CH₂— piperidin-1,3- bond 2,4-diCl-phenyl diyl  448 —CH₂— piperidin-1,3- bond 2,5-diCl-phenyl diyl  449 —CH₂— piperidin-1,3- bond 2,6-diCl-phenyl diyl  450 —CH₂— piperidin-1,3- bond 3,4-diCl-phenyl diyl  451 —CH₂— piperidin-1,3- bond 3,5-diCl-phenyl diyl  452 —CH₂— piperidin-1,3- bond 2-Cl-3-F-phenyl diyl  453 —CH₂— piperidin-1,3- bond 2-Cl-4-F-phenyl diyl  454 —CH₂— piperidin-1,3- bond 2-Cl-5-F-phenyl diyl  455 —CH₂— piperidin-1,3- bond 3-Cl-4-F-phenyl diyl  456 —CH₂— piperidin-1,3- bond 3-Cl-5-F-phenyl diyl  457 —CH₂— piperidin-1,3- bond 4-Cl-2-F-phenyl diyl  458 —CH₂— piperidin-1,3- bond 4-Cl-3-F-phenyl diyl  459 —CH₂— piperidin-1,3- bond 2,3-diMeO- diyl phenyl  460 —CH₂— piperidin-1,3- bond 2,4-diMeO- diyl phenyl  461 —CH₂— piperidin-1,3- bond 2,5-diMeO- diyl phenyl  462 —CH₂— piperidin-1,3- bond 2,6-diMeO- diyl phenyl  463 —CH₂— piperidin-1,3- bond 3,4-diMeO- diyl phenyl  464 —CH₂— piperidin-1,3- bond 3,5-diMeO- diyl phenyl  465 —CH₂— piperidin-1,3- bond cyclopropyl diyl  466 —CH₂— piperidin-1,3- bond cyclobutyl diyl  467 —CH₂— piperidin-1,3- bond cyclopentyl diyl  468 —CH₂— piperidin-1,3- bond cyclohexyl diyl  469 —CH₂— piperidin-1,3- bond 2-furanyl diyl  470 —CH₂— piperidin-1,3- bond 2-thienyl diyl  471 —CH₂— piperidin-1,3- bond 2-imidazolyl diyl  472 —CH₂— piperidin-1,3- bond 2-pyridyl diyl  473 —CH₂— piperidin-1,3- bond 3-pyridyl diyl  474 —CH₂— piperidin-1,3- bond 4-pyridyl diyl  475 —CH₂— piperidin-1,3- bond N-morpholinyl diyl  476 —CH₂— piperidin-1,3- bond N-piperidinyl diyl  477 —CH₂— piperidin-1,3- bond 3-Me-2-pyridyl diyl  478 —CH₂— piperidin-1,3- bond 4-Me-2-pyridyl diyl  479 —CH₂— piperidin-1,3- bond 1-indolyl diyl  480 —CH₂— piperidin-1,3- bond 2-benzothienyl diyl  481 —CH₂— piperidin-1,3- bond 2-benzofuranyl diyl  482 —CH₂— piperidin-1,3- bond 1-benzimidazole diyl  483 —CH₂— piperidin-1,3- bond 2-naphthyl diyl  484 —CH₂— piperidin-3,1- bond phenyl diyl  485 —CH₂— piperidin-3,1- bond 3,3- diyl diphenylmethyl  486 —CH₂— piperidin-3,1- bond 2-F-phenyl diyl  487 —CH₂— piperidin-3,1- bond 3-F-phenyl diyl  488 —CH₂— piperidin-3,1- bond 4-F-phenyl diyl  489 —CH₂— piperidin-3,1- bond 2-Cl-phenyl diyl  490 —CH₂— piperidin-3,1- bond 3-Cl-phenyl diyl  491 —CH₂— piperidin-3,1- bond 4-Cl-phenyl diyl  492 —CH₂— piperidin-3,1- bond 2-Me-phenyl diyl  493 —CH₂— piperidin-3,1- bond 3-Me-phenyl diyl  494 —CH₂— piperidin-3,1- bond 4-Me-phenyl diyl  495 —CH₂— piperidin-3,1- bond 2-MeO-phenyl diyl  496 —CH₂— piperidin-3,1- bond 3-MeO-phenyl diyl  497 —CH₂— piperidin-3,1- bond 4-MeO-phenyl diyl  498 —CH₂— piperidin-3,1- bond 2-MeS-phenyl diyl  499 —CH₂— piperidin-3,1- bond 3-MeS-phenyl diyl  500 —CH₂— piperidin-3,1- bond 4-MeS-phenyl diyl  501 —CH₂— piperidin-3,1- bond 2-F₃C-phenyl diyl  502 —CH₂— piperidin-3,1- bond 3-F₃C-phenyl diyl  503 —CH₂— piperidin-3,1- bond 4-F₃C-phenyl diyl  504 —CH₂— piperidin-3,1- bond 2,3-diF-phenyl diyl  505 —CH₂— piperidin-3,1- bond 2,4-diF-phenyl diyl  506 —CH₂— piperidin-3,1- bond 2,5-diF-phenyl diyl  507 —CH₂— piperidin-3,1- bond 2,6-diF-phenyl diyl  508 —CH₂— piperidin-3,1- bond 3,4-diF-phenyl diyl  509 —CH₂— piperidin-3,1- bond 3,5-diF-phenyl diyl  510 —CH₂— piperidin-3,1- bond 2,3-diCl-phenyl diyl  511 —CH₂— piperidin-3,1- bond 2,4-diCl-phenyl diyl  512 —CH₂— piperidin-3,1- bond 2,5-diCl-phenyl diyl  513 —CH₂— piperidin-3,1- bond 2,6-diCl-phenyl diyl  514 —CH₂— piperidin-3,1- bond 3,4-diCl-phenyl diyl  515 —CH₂— piperidin-3,1- bond 3,5-diCl-phenyl diyl  516 —CH₂— piperidin-3,1- bond 2-Cl-3-F-phenyl diyl  517 —CH₂— piperidin-3,1- bond 2-Cl-4-F-phenyl diyl  518 —CH₂— piperidin-3,1- bond 2-Cl-5-F-phenyl diyl  519 —CH₂— piperidin-3,1- bond 3-Cl-4-F-phenyl diyl  520 —CH₂— piperidin-3,1- bond 3-Cl-5-F-phenyl diyl  521 —CH₂— piperidin-3,1- bond 4-Cl-2-F-phenyl diyl  522 —CH₂— piperidin-3,1- bond 4-Cl-3-F-phenyl diyl  523 —CH₂— piperidin-3,1- bond 2,3-diMeO- diyl phenyl  524 —CH₂— piperidin-3,1- bond 2,4-diMeO- diyl phenyl  525 —CH₂— piperidin-3,1- bond 2,5-diMeO- diyl phenyl  526 —CH₂— piperidin-3,1- bond 2,6-diMeO- diyl phenyl  527 —CH₂— piperidin-3,1- bond 3,4-diMeO- diyl phenyl  528 —CH₂— piperidin-3,1- bond 3,5-diMeO- diyl phenyl  529 —CH₂— piperidin-3,1- bond cyclopropyl diyl  530 —CH₂— piperidin-3,1- bond cyclobutyl diyl  531 —CH₂— piperidin-3,1- bond cyclopentyl diyl  532 —CH₂— piperidin-3,1- bond cyclohexyl diyl  533 —CH₂— piperidin-3,1 bond 2-furanyl diyl  534 —CH₂— piperidin-3,1- bond 2-thienyl diyl  535 —CH₂— piperidin-3,1- bond 2-imidazolyl diyl  536 —CH₂— piperidin-3,1- bond 2-pyridyl diyl  537 —CH₂— piperidin-3,1- bond 3-pyridyl diyl  538 —CH₂— piperidin-3,1- bond 4-pyridyl diyl  539 —CH₂— piperidin-3,1- bond N-morpholinyl diyl  540 —CH₂— piperidin-3,1- bond N-piperidinyl diyl  541 —CH₂— piperidin-3,1- bond 3-Me-2-pyridyl diyl  542 —CH₂— piperidin-3,1- bond 4-Me-2-pyridyl diyl  543 —CH₂— piperidin-3,1- bond 1-indolyl diyl  544 —CH₂— piperidin-3,1- bond 2-benzothienyl diyl  545 —CH₂— piperidin-3,1- bond 2-benzofuranyl diyl  546 —CH₂— piperidin-3,1- bond 1-benzimidazole diyl  547 —CH₂— piperidin-3,1- bond 2-naphthyl diyl  548 —CH₂— cyclohex-1,3- bond phenyl diyl  549 —CH₂— cyclohex-1,3- bond 3,3- diyl diphenylmethyl  550 —CH₂— cyclohex-1,3- bond 2-F-phenyl diyl  551 —CH₂— cyclohex-1,3- bond 3-F-phenyl diyl  552 —CH₂— cyclohex-1,3- bond 4-F-phenyl diyl  553 —CH₂— cyclohex-1,3- bond 2-Cl-phenyl diyl  554 —CH₂— cyclohex-1,3- bond 3-Cl-phenyl diyl  555 —CH₂— cyclohex-1,3- bond 4-Cl-phenyl diyl  556 —CH₂— cyclohex-1,3- bond 2-Me-phenyl diyl  557 —CH₂— cyclohex-1,3- bond 3-Me-phenyl diyl  558 —CH₂— cyclohex-1,3- bond 4-Me-phenyl diyl  559 —CH₂— cyclohex-1,3- bond 2-MeO-phenyl diyl  560 —CH₂— cyclohex-1,3- bond 3-MeO-phenyl diyl  561 —CH₂— cyclohex-1,3- bond 4-MeO-phenyl diyl  562 —CH₂— cyclohex-1,3- bond 2-MeS-phenyl diyl  563 —CH₂— cyclohex-1,3- bond 3-MeS-phenyl diyl  564 —CH₂— cyclohex-1,3- bond 4-MeS-phenyl diyl  565 —CH₂— cyclohex-1,3- bond 2-F₃C-phenyl diyl  566 —CH₂— cyclohex-1,3- bond 3-F₃C-phenyl diyl  567 —CH₂— cyclohex-1,3- bond 4-F₃C-phenyl diyl  568 —CH₂— cyclohex-1,3- bond 2,3-diF-phenyl diyl  569 —CH₂— cyclohex-1,3- bond 2,4-diF-phenyl diyl  570 —CH₂— cyclohex-1,3- bond 2,5-diF-phenyl diyl  571 —CH₂— cyclohex-1,3- bond 2,6-diF-phenyl diyl  572 —CH₂— cyclohex-1,3- bond 3,4-diF-phenyl diyl  573 —CH₂— cyclohex-1,3- bond 3,5-diF-phenyl diyl  574 —CH₂— cyclohex-1,3- bond 2,3-diCl-phenyl diyl  575 —CH₂— cyclohex-1,3- bond 2,4-diCl-phenyl diyl  576 —CH₂— cyclohex-1,3- bond 2,5-diCl-phenyl diyl  577 —CH₂— cyclohex-1,3- bond 2,6-diCl-phenyl diyl  578 —CH₂— cyclohex-1,3- bond 3,4-diCl-phenyl diyl  579 —CH₂— cyclohex-1,3- bond 3,5-diCl-phenyl diyl  580 —CH₂— cyclohex-1,3- bond 2-Cl-3-F-phenyl diyl  581 —CH₂— cyclohex-1,3- bond 2-Cl-4-F-phenyl diyl  582 —CH₂— cyclohex-1,3- bond 2-Cl-5-F-phenyl diyl  583 —CH₂— cyclohex-1,3- bond 3-Cl-4-F-phenyl diyl  584 —CH₂— cyclohex-1,3- bond 3-Cl-5-F-phenyl diyl  585 —CH₂— cyclohex-1,3- bond 4-Cl-2-F-phenyl diyl  586 —CH₂— cyclohex-1,3- bond 4-Cl-3-F-phenyl diyl  587 —CH₂— cyclohex-1,3- bond 2,3-diMeO- diyl phenyl  588 —CH₂— cyclohex-1,3- bond 2,4-diMeO- diyl phenyl  589 —CH₂— cyclohex-1,3- bond 2,5-diMeO- diyl phenyl  590 —CH₂— cyclohex-1,3- bond 2,6-diMeO- diyl phenyl  591 —CH₂— cyclohex-1,3- bond 3,4-diMeO- diyl phenyl  592 —CH₂— cyclohex-1,3- bond 3,5-diMeO- diyl phenyl  593 —CH₂— cyclohex-1,3- bond cyclopropyl diyl  594 —CH₂— cyclohex-1,3- bond cyclobutyl diyl  595 —CH₂— cyclohex-1,3- bond cyclopentyl diyl  596 —CH₂— cyclohex-1,3- bond cyclohexyl diyl  597 —CH₂— cyclohex-1,3- bond 2-furanyl diyl  598 —CH₂— cyclohex-1,3- bond 2-thienyl diyl  599 —CH₂— cyclohex-1,3- bond 2-imidazolyl diyl  600 —CH₂— cyclohex-1,3- bond 2-pyridyl diyl  601 —CH₂— cyclohex-1,3- bond 3-pyridyl diyl  602 —CH₂— cyclohex-1,3- bond 4-pyridyl diyl  603 —CH₂— cyclohex-1,3- bond N-morpholinyl diyl  604 —CH₂— cyclohex-1,3- bond N-piperidinyl diyl  605 —CH₂— cyclohex-1,3- bond 3-Me-2-pyridyl diyl  606 —CH₂— cyclohex-1,3- bond 4-Me-2-pyridyl diyl  607 —CH₂— cyclohex-1,3- bond 1-indolyl diyl  608 —CH₂— cyclohex-1,3- bond 2-benzothienyl diyl  609 —CH₂— cyclohex-1,3- bond 2-benzofuranyl diyl  610 —CH₂— cyclohex-1,3- bond 1-benzimidazole diyl  611 —CH₂— cyclohex-1,3- bond 2-naphthyl diyl  612 —CH₂— cyclopropan- bond phenyl 1,2-diyl  613 —CH₂— cyclopropan- bond 3,3- 1,2-diyl diphenylmethyl  614 —CH₂— cyclopropan- bond 2-F-phenyl 1,2-diyl  615 —CH₂— cyclopropan- bond 3-F-phenyl 1,2-diyl  616 —CH₂— cyclopropan- bond 4-F-phenyl 1,2-diyl  617 —CH₂— cyclopropan- bond 2-Cl-phenyl 1,2-diyl  618 —CH₂— cyclopropan- bond 3-Cl-phenyl 1,2-diyl  619 —CH₂— cyclopropan- bond 4-Cl-phenyl 1,2-diyl  620 —CH₂— cyclopropan- bond 2-Me-phenyl 1,2-diyl  621 —CH₂— cyclopropan- bond 3-Me-phenyl 1,2-diyl  622 —CH₂— cyclopropan- bond 4-Me-phenyl 1,2-diyl  623 —CH₂— cyclopropan- bond 2-MeO-phenyl 1,2-diyl  624 —CH₂— cyclopropan- bond 3-MeO-phenyl 1,2-diyl  625 —CH₂— cyclopropan- bond 4-MeO-phenyl 1,2-diyl  626 —CH₂— cyclopropan- bond 2-MeS-phenyl 1,2-diyl  627 —CH₂— cyclopropan- bond 3-MeS-phenyl 1,2-diyl  628 —CH₂— cyclopropan- bond 4-MeS-phenyl 1,2-diyl  629 —CH₂— cyclopropan- bond 2-F₃C-phenyl 1,2-diyl  630 —CH₂— cyclopropan- bond 3-F₃C-phenyl 1,2-diyl  631 —CH₂— cyclopropan- bond 4-F₃C-phenyl 1,2-diyl  632 —CH₂— cyclopropan- bond 2,3-diF-phenyl 1,2-diyl  633 —CH₂— cyclopropan- bond 2,4-diF-phenyl 1,2-diyl  634 —CH₂— cyclopropan- bond 2,5-diF-phenyl 1,2-diyl  635 —CH₂— cyclopropan- bond 2,6-diF-phenyl 1,2-diyl  636 —CH₂— cyclopropan- bond 3,4-diF-phenyl 1,2-diyl  637 —CH₂— cyclopropan- bond 3,5-diF-phenyl 1,2-diyl  638 —CH₂— cyclopropan- bond 2,3-diCl-phenyl 1,2-diyl  639 —CH₂— cyclopropan- bond 2,4-diCl-phenyl 1,2-diyl  640 —CH₂— cyclopropan- bond 2,5-diCl-phenyl 1,2-diyl  641 —CH₂— cyclopropan- bond 2,6-diCl-phenyl 1,2-diyl  642 —CH₂— cyclopropan- bond 3,4-diCl-phenyl 1,2-diyl  643 —CH₂— cyclopropan- bond 3,5-diCl-phenyl 1,2-diyl  644 —CH₂— cyclopropan- bond 2-Cl-3-F-phenyl 1,2-diyl  645 —CH₂— cyclopropan- bond 2-Cl-4-F-phenyl 1,2-diyl  646 —CH₂— cyclopropan- bond 2-Cl-5-F-phenyl 1,2-diyl  647 —CH₂— cyclopropan- bond 3-Cl-4-F-phenyl 1,2-diyl  648 —CH₂— cyclopropan- bond 3-Cl-5-F-phenyl 1,2-diyl  649 —CH₂— cyclopropan- bond 4-Cl-2-F-phenyl 1,2-diyl  650 —CH₂— cyclopropan- bond 4-Cl-3-F-phenyl 1,2-diyl  651 —CH₂— cyclopropan- bond 2,3-diMeO- 1,2-diyl phenyl  652 —CH₂— cyclopropan- bond 2,4-diMeO- 1,2-diyl phenyl  653 —CH₂— cyclopropan- bond 2,5-diMeO- 1,2-diyl phenyl  654 —CH₂— cyclopropan- bond 2,6-diMeO- 1,2-diyl phenyl  655 —CH₂— cyclopropan- bond 3,4-diMeO- 1,2-diyl phenyl  656 —CH₂— cyclopropan- bond 3,5-diMeO- 1,2-diyl phenyl  657 —CH₂— cyclopropan- bond cyclopropyl 1,2-diyl  658 —CH₂— cyclopropan- bond cyclobutyl 1,2-diyl  659 —CH₂— cyclopropan- bond cyclopentyl 1,2-diyl  660 —CH₂— cyclopropan- bond cyclohexyl 1,2-diyl  661 —CH₂— cyclopropan- bond 2-furanyl 1,2-diyl  662 —CH₂— cyclopropan- bond 2-thienyl 1,2-diyl  663 —CH₂— cyclopropan- bond 2-imidazolyl 1,2-diyl  664 —CH₂— cyclopropan- bond 2-pyridyl 1,2-diyl  665 —CH₂— cyclopropan- bond 3-pyridyl 1,2-diyl  666 —CH₂— cyclopropan- bond 4-pyridyl 1,2-diyl  667 —CH₂— cyclopropan- bond N-morpholinyl 1,2-diyl  668 —CH₂— cyclopropan- bond N-piperidinyl 1,2-diyl  669 —CH₂— cyclopropan- bond 3-Me-2-pyridyl 1,2-diyl  670 —CH₂— cyclopropan- bond 4-Me-2-pyridyl 1,2-diyl  671 —CH₂— cyclopropan- bond 1-indolyl 1,2-diyl  672 —CH₂— cyclopropan- bond 2-benzothienyl 1,2-diyl  673 —CH₂— cyclopropan- bond 2-benzofuranyl 1,2-diyl  674 —CH₂— cyclopropan- bond 1-benzimidazole 1,2-diyl  675 —CH₂— cyclopropan- bond 2-naphthyl 1,2-diyl  676 —CH₂— cyclopentan- bond phenyl 1,3-diyl  677 —CH₂— cyclopentan- bond 3,3- 1,3-diyl diphenylmethyl  678 —CH₂— cyclopentan- bond 2-F-phenyl 1,3-diyl  679 —CH₂— cyclopentan- bond 3-F-phenyl 1,3-diyl  680 —CH₂— cyclopentan- bond 4-F-phenyl 1,3-diyl  681 —CH₂— cyclopentan- bond 2-Cl-phenyl 1,3-diyl  682 —CH₂— cyclopentan- bond 3-Cl-phenyl 1,3-diyl  683 —CH₂— cyclopentan- bond 4-Cl-phenyl 1,3-diyl  684 —CH₂— cyclopentan- bond 2-Me-phenyl 1,3-diyl  685 —CH₂— cyclopentan- bond 3-Me-phenyl 1,3-diyl  686 —CH₂— cyclopentan- bond 4-Me-phenyl 1,3-diyl  687 —CH₂— cyclopentan- bond 2-MeO-phenyl 1,3-diyl  688 —CH₂— cyclopentan- bond 3-MeO-phenyl 1,3-diyl  689 —CH₂— cyclopentan- bond 4-MeO-phenyl 1,3-diyl  690 —CH₂— cyclopentan- bond 2-MeS-phenyl 1,3-diyl  691 —CH₂— cyclopentan- bond 3-MeS-phenyl 1,3-diyl  692 —CH₂— cyclopentan- bond 4-MeS-phenyl 1,3-diyl  693 —CH₂— cyclopentan- bond 2-F₃C-phenyl 1,3-diyl  694 —CH₂— cyclopentan- bond 3-F₃C-phenyl 1,3-diyl  695 —CH₂— cyclopentan- bond 4-F₃C-phenyl 1,3-diyl  696 —CH₂— cyclopentan- bond 2,3-diF-phenyl 1,3-diyl  697 —CH₂— cyclopentan- bond 2,4-diF-phenyl 1,3-diyl  698 —CH₂— cyclopentan- bond 2,5-diF-phenyl 1,3-diyl  699 —CH₂— cyclopentan- bond 2,6-diF-phenyl 1,3-diyl  700 —CH₂— cyclopentan- bond 3,4-diF-phenyl 1,3-diyl  701 —CH₂— cyclopentan- bond 3,5-diF-phenyl 1,3-diyl  702 —CH₂— cyclopentan- bond 2,3-diCl-phenyl 1,3-diyl  703 —CH₂— cyclopentan- bond 2,4-diCl-phenyl 1,3-diyl  704 —CH₂— cyclopentan- bond 2,5-diCl-phenyl 1,3-diyl  705 —CH₂— cyclopentan- bond 2,6-diCl-phenyl 1,3-diyl  706 —CH₂— cyclopentan- bond 3,4-diCl-phenyl 1,3-diyl  707 —CH₂— cyclopentan- bond 3,5-diCl-phenyl 1,3-diyl  708 —CH₂— cyclopentan- bond 2-Cl-3-F-phenyl 1,3-diyl  709 —CH₂— cyclopentan- bond 2-Cl-4-F-phenyl 1,3-diyl  710 —CH₂— cyclopentan- bond 2-Cl-5-F-phenyl 1,3-diyl  711 —CH₂— cyclopentan- bond 3-Cl-4-F-phenyl 1,3-diyl  712 —CH₂— cyclopentan- bond 3-Cl-5-F-phenyl 1,3-diyl  713 —CH₂— cyclopentan- bond 4-Cl-2-F-phenyl 1,3-diyl  714 —CH₂— cyclopentan- bond 4-Cl-3-F-phenyl 1,3-diyl  715 —CH₂— cyclopentan- bond 2,3-diMeO- 1,3-diyl phenyl  716 —CH₂— cyclopentan- bond 2,4-diMeO- 1,3-diyl phenyl  717 —CH₂— cyclopentan- bond 2,5-diMeO- 1,3-diyl phenyl  718 —CH₂— cyclopentan- bond 2,6-diMeO- 1,3-diyl phenyl  719 —CH₂— cyclopentan- bond 3,4-diMeO- 1,3-diyl phenyl  720 —CH₂— cyclopentan- bond 3,5-diMeO- 1,3-diyl phenyl  721 —CH₂— cyclopentan- bond cyclopropyl 1,3-diyl  722 —CH₂— cyclopentan- bond cyclobutyl 1,3-diyl  723 —CH₂— cyclopentan- bond cyclopentyl 1,3-diyl  724 —CH₂— cyclopentan- bond cyclohexyl 1,3-diyl  725 —CH₂— cyclopentan- bond 2-furanyl 1,3-diyl  726 —CH₂— cyclopentan- bond 2-thienyl 1,3-diyl  727 —CH₂— cyclopentan- bond 2-imidazolyl 1,3-diyl  728 —CH₂— cyclopentan- bond 2-pyridyl 1,3-diyl  729 —CH₂— cyclopentan- bond 3-pyridyl 1,3-diyl  730 —CH₂— cyclopentan- bond 4-pyridyl 1,3-diyl  731 —CH₂— cyclopentan- bond N-morpholinyl 1,3-diyl  732 —CH₂— cyclopentan- bond N-piperidinyl 1,3-diyl  733 —CH₂— cyclopentan- bond 3-Me-2-pyridyl 1,3-diyl  734 —CH₂— cyclopentan- bond 4-Me-2-pyridyl 1,3-diyl  735 —CH₂— cyclopentan- bond 1-indolyl 1,3-diyl  736 —CH₂— cyclopentan- bond 2-benzothienyl 1,3-diyl  737 —CH₂— cyclopentan- bond 2-benzofuranyl 1,3-diyl  738 —CH₂— cyclopentan- bond 1-benzimidazole 1,3-diyl  739 —CH₂— cyclopentan- bond 2-naphthyl 1,3-diyl  740 —CH₂— phen-1,3-diyl —O— phenyl  741 —CH₂— phen-1,3-diyl —O— 3,3- diphenylmethyl  742 —CH₂— phen-1,3-diyl —O— 2-F-phenyl  743 —CH₂— phen-1,3-diyl —O— 3-F-phenyl  744 —CH₂— phen-1,3-diyl —O— 4-F-phenyl  745 —CH₂— phen-1,3-diyl —O— 2-Cl-phenyl  746 —CH₂— phen-1,3-diyl —O— 3-Cl-phenyl  747 —CH₂— phen-1,3-diyl —O— 4-Cl-phenyl  748 —CH₂— phen-1,3-diyl —O— 2-Me-phenyl  749 —CH₂— phen-1,3-diyl —O— 3-Me-phenyl  750 —CH₂— phen-1,3-diyl —O— 4-Me-phenyl  751 —CH₂— phen-1,3-diyl —O— 2-MeO-phenyl  752 —CH₂— phen-1,3-diyl —O— 3-MeO-phenyl  753 —CH₂— phen-1,3-diyl —O— 4-MeO-phenyl  754 —CH₂— phen-1,3-diyl —O— 2-MeS-phenyl  755 —CH₂— phen-1,3-diyl —O— 3-MeS-phenyl  756 —CH₂— phen-1,3-diyl —O— 4-MeS-phenyl  757 —CH₂— phen-1,3-diyl —O— 2-F₃C-phenyl  758 —CH₂— phen-1,3-diyl —O— 3-F₃C-phenyl  759 —CH₂— phen-1,3-diyl —O— 4-F₃C-phenyl  760 —CH₂— phen-1,3-diyl —O— 2,3-diF-phenyl  761 —CH₂— phen-1,3-diyl —O— 2,4-diF-phenyl  762 —CH₂— phen-1,3-diyl —O— 2,5-diF-phenyl  763 —CH₂— phen-1,3-diyl —O— 2,6-diF-phenyl  764 —CH₂— phen-1,3-diyl —O— 3,4-diF-phenyl  765 —CH₂— phen-1,3-diyl —O— 3,5-diF-phenyl  766 —CH₂— phen-1,3-diyl —O— 2,3-diCl-phenyl  767 —CH₂— phen-1,3-diyl —O— 2,4-diCl-phenyl  768 —CH₂— phen-1,3-diyl —O— 2,5-diCl-phenyl  769 —CH₂— phen-1,3-diyl —O— 2,6-diCl-phenyl  770 —CH₂— phen-1,3-diyl —O— 3,4-diCl-phenyl  771 —CH₂— phen-1,3-diyl —O— 3,5-diCl-phenyl  772 —CH₂— phen-1,3-diyl —O— 2-Cl-3-F-phenyl  773 —CH₂— phen-1,3-diyl —O— 2-Cl-4-F-phenyl  774 —CH₂— phen-1,3-diyl —O— 2-Cl-5-F-phenyl  775 —CH₂— phen-1,3-diyl —O— 3-Cl-4-F-phenyl  776 —CH₂— phen-1,3-diyl —O— 3-Cl-5-F-phenyl  777 —CH₂— phen-1,3-diyl —O— 4-Cl-2-F-phenyl  778 —CH₂— phen-1,3-diyl —O— 4-Cl-3-F-phenyl  779 —CH₂— phen-1,3-diyl —O— 2,3-diMeO- phenyl  780 —CH₂— phen-1,3-diyl —O— 2,4-diMeO- phenyl  781 —CH₂— phen-1,3-diyl —O— 2,5-diMeO- phenyl  782 —CH₂— phen-1,3-diyl —O— 2,6-diMeO- phenyl  783 —CH₂— phen-1,3-diyl —O— 3,4-diMeO- phenyl  784 —CH₂— phen-1,3-diyl —O— 3,5-diMeO- phenyl  785 —CH₂— phen-1,3-diyl —O— cyclopropyl  786 —CH₂— phen-1,3-diyl —O— cyclobutyl  787 —CH₂— phen-1,3-diyl —O— cyclopentyl  788 —CH₂— phen-1,3-diyl —O— cyclohexyl  789 —CH₂— phen-1,3-diyl —O— 2-furanyl  790 —CH₂— phen-1,3-diyl —O— 2-thienyl  791 —CH₂— phen-1,3-diyl CH₂CH₂ 2-imidazolyl  792 —CH₂— phen-1,3-diyl —O— 2-pyridyl  793 —CH₂— phen-1,3-diyl —O— 3-pyridyl  794 —CH₂— phen-1,3-diyl —O— 4-pyridyl  795 —CH₂— phen-1,3-diyl CH₂CH₂ N-morpholinyl  796 —CH₂— phen-1,3-diyl CH₂CH₂ N-piperidinyl  797 —CH₂— phen-1,3-diyl —O— 3-Me-2-pyridyl  798 —CH₂— phen-1,3-diyl —O— 4-Me-2-pyridyl  799 —CH₂— phen-1,3-diyl CH₂CH₂ 1-indolyl  800 —CH₂— phen-1,3-diyl —O— 2-benzothienyl  801 —CH₂— phen-1,3-diyl —O— 2-benzofuranyl  802 —CH₂— phen-1,3-diyl CH₂CH₂ 1-benzimidazole  803 —CH₂— phen-1,3-diyl —O— 2-naphthyl  804 —CH₂— pyridin-3,5-diyl —O— phenyl  805 —CH₂— pyridin-3,5-diyl —O— 3,3- diphenylmethyl  806 —CH₂— pyridin-3,5-diyl —O— 2-F-phenyl  807 —CH₂— pyridin-3,5-diyl —O— 3-F-phenyl  808 —CH₂— pyridin-3,5-diyl —O— 4-F-phenyl  809 —CH₂— pyridin-3,5-diyl —O— 2-Cl-phenyl  810 —CH₂— pyridin-3,5-diyl —O— 3-Cl-phenyl  811 —CH₂— pyridin-3,5-diyl —O— 4-Cl-phenyl  812 —CH₂— pyridin-3,5-diyl —O— 2-Me-phenyl  813 —CH₂— pyridin-3,5-diyl —O— 3-Me-phenyl  814 —CH₂— pyridin-3,5-diyl —O— 4-Me-phenyl  815 —CH₂— pyridin-3,5-diyl —O— 2-MeO-phenyl  816 —CH₂— pyridin-3,5-diyl —O— 3-MeO-phenyl  817 —CH₂— pyridin-3,5-diyl —O— 4-MeO-phenyl  818 —CH₂— pyridin-3,5-diyl —O— 2-MeS-phenyl  819 —CH₂— pyridin-3,5-diyl —O— 3-MeS-phenyl  820 —CH₂— pyridin-3,5-diyl —O— 4-MeS-phenyl  821 —CH₂— pyridin-3,5-diyl —O— 2-F₃C-phenyl  822 —CH₂— pyridin-3,5-diyl —O— 3-F₃C-phenyl  823 —CH₂— pyridin-3,5-diyl —O— 4-F₃C-phenyl  824 —CH₂— pyridin-3,5-diyl —O— 2,3-diF-phenyl  825 —CH₂— pyridin-3,5-diyl —O— 2,4-diF-phenyl  826 —CH₂— pyridin-3,5-diyl —O— 2,5-diF-phenyl  827 —CH₂— pyridin-3,5-diyl —O— 2,6-diF-phenyl  828 —CH₂— pyridin-3,5-diyl —O— 3,4-diF-phenyl  829 —CH₂— pyridin-3,5-diyl —O— 3,5-diF-phenyl  830 —CH₂— pyridin-3,5-diyl —O— 2,3-diCl-phenyl  831 —CH₂— pyridin-3,5-diyl —O— 2,4-diCl-phenyl  832 —CH₂— pyridin-3,5-diyl —O— 2,5-diCl-phenyl  833 —CH₂— pyridin-3,5-diyl —O— 2,6-diCl-phenyl  834 —CH₂— pyridin-3,5-diyl —O— 3,4-diCl-phenyl  835 —CH₂— pyridin-3,5-diyl —O— 3,5-diCl-phenyl  836 —CH₂— pyridin-3,5-diyl —O— 2-Cl-3-F-phenyl  837 —CH₂— pyridin-3,5-diyl —O— 2-Cl-4-F-phenyl  838 —CH₂— pyridin-3,5-diyl —O— 2-Cl-5-F-phenyl  839 —CH₂— pyridin-3,5-diyl —O— 3-Cl-4-F-phenyl  840 —CH₂— pyridin-3,5-diyl —O— 3-Cl-5-F-phenyl  841 —CH₂— pyridin-3,5-diyl —O— 4-Cl-2-F-phenyl  842 —CH₂— pyridin-3,5-diyl —O— 4-Cl-3-F-phenyl  843 —CH₂— pyridin-3,5-diyl —O— 2,3-diMeO- phenyl  844 —CH₂— pyridin-3,5-diyl —O— 2,4-diMeO- phenyl  845 —CH₂— pyridin-3,5-diyl —O— 2,5-diMeO- phenyl  846 —CH₂— pyridin-3,5-diyl —O— 2,6-diMeO- phenyl  847 —CH₂— pyridin-3,5-diyl —O— 3,4-diMeO- phenyl  848 —CH₂— pyridin-3,5-diyl —O— 3,5-diMeO- phenyl  849 —CH₂— pyridin-3,5-diyl —O— cyclopropyl  850 —CH₂— pyridin-3,5-diyl —O— cyclobutyl  851 —CH₂— pyridin-3,5-diyl —O— cyclopentyl  852 —CH₂— pyridin-3,5-diyl —O— cyclohexyl  853 —CH₂— pyridin-3,5-diyl —O— 2-furanyl  854 —CH₂— pyridin-3,5-diyl —O— 2-thienyl  855 —CH₂— pyridin-3,5-diyl CH₂CH₂ 2-imidazolyl  856 —CH₂— pyridin-3,5-diyl —O— 2-pyridyl  857 —CH₂— pyridin-3,5-diyl —O— 3-pyridyl  858 —CH₂— pyridin-3,5-diyl —O— 4-pyridyl  859 —CH₂— pyridin-3,5-diyl CH₂CH₂ N-morpholinyl  860 —CH₂— pyridin-3,5-diyl CH₂CH₂ N-piperidinyl  861 —CH₂— pyridin-3,5-diyl —O— 3-Me-2-pyridyl  862 —CH₂— pyridin-3,5-diyl —O— 4-Me-2-pyridyl  863 —CH₂— pyridin-3,5-diyl CH₂CH₂ 1-indolyl  864 —CH₂— pyridin-3,5-diyl —O— 2-benzothienyl  865 —CH₂— pyridin-3,5-diyl —O— 2-benzofuranyl  866 —CH₂— pyridin-3,5-diyl CH₂CH₂ 1-benzimidazole  867 —CH₂— pyridin-3,5-diyl —O— 2-naphthyl  868 —CH₂— pyridin-2,6-diyl —O— phenyl  869 —CH₂— pyridin-2,6-diyl —O— 3,3- diphenylmethyl  870 —CH₂— pyridin-2,6-diyl —O— 2-F-phenyl  871 —CH₂— pyridin-2,6-diyl —O— 3-F-phenyl  872 —CH₂— pyridin-2,6-diyl —O— 4-F-phenyl  873 —CH₂— pyridin-2,6-diyl —O— 2-Cl-phenyl  874 —CH₂— pyridin-2,6-diyl —O— 3-Cl-phenyl  875 —CH₂— pyridin-2,6-diyl —O— 4-Cl-phenyl  876 —CH₂— pyridin-2,6-diyl —O— 2-Me-phenyl  877 —CH₂— pyridin-2,6-diyl —O— 3-Me-phenyl  878 —CH₂— pyridin-2,6-diyl —O— 4-Me-phenyl  879 —CH₂— pyridin-2,6-diyl —O— 2-MeO-phenyl  880 —CH₂— pyridin-2,6-diyl —O— 3-MeO-phenyl  881 —CH₂— pyridin-2,6-diyl —O— 4-MeO-phenyl  882 —CH₂— pyridin-2,6-diyl —O— 2-MeS-phenyl  883 —CH₂— pyridin-2,6-diyl —O— 3-MeS-phenyl  884 —CH₂— pyridin-2,6-diyl —O— 4-MeS-phenyl  885 —CH₂— pyridin-2,6-diyl —O— 2-F₃C-phenyl  886 —CH₂— pyridin-2,6-diyl —O— 3-F₃C-phenyl  887 —CH₂— pyridin-2,6-diyl —O— 4-F₃C-phenyl  888 —CH₂— pyridin-2,6-diyl —O— 2,3-diF-phenyl  889 —CH₂— pyridin-2,6-diyl —O— 2,4-diF-phenyl  890 —CH₂— pyridin-2,6-diyl —O— 2,5-diF-phenyl  891 —CH₂— pyridin-2,6-diyl —O— 2,6-diF-phenyl  892 —CH₂— pyridin-2,6-diyl —O— 3,4-diF-phenyl  893 —CH₂— pyridin-2,6-diyl —O— 3,5-diF-phenyl  894 —CH₂— pyridin-2,6-diyl —O— 2,3-diCl-phenyl  895 —CH₂— pyridin-2,6-diyl —O— 2,4-diCl-phenyl  896 —CH₂— pyridin-2,6-diyl —O— 2,5-diCl-phenyl  897 —CH₂— pyridin-2,6-diyl —O— 2,6-diCl-phenyl  898 —CH₂— pyridin-2,6-diyl —O— 3,4-diCl-phenyl  899 —CH₂— pyridin-2,6-diyl —O— 3,5-diCl-phenyl  900 —CH₂— pyridin-2,6-diyl —O— 2-Cl-3-F-phenyl  901 —CH₂— pyridin-2,6-diyl —O— 2-Cl-4-F-phenyl  902 —CH₂— pyridin-2,6-diyl —O— 2-Cl-5-F-phenyl  903 —CH₂— pyridin-2,6-diyl —O— 3-Cl-4-F-phenyl  904 —CH₂— pyridin-2,6-diyl —O— 3-Cl-5-F-phenyl  905 —CH₂— pyridin-2,6-diyl —O— 4-Cl-2-F-phenyl  906 —CH₂— pyridin-2,6-diyl —O— 4-Cl-3-F-phenyl  907 —CH₂— pyridin-2,6-diyl —O— 2,3-diMeO- phenyl  908 —CH₂— pyridin-2,6-diyl —O— 2,4-diMeO- phenyl  909 —CH₂— pyridin-2,6-diyl —O— 2,5-diMeO- phenyl  910 —CH₂— pyridin-2,6-diyl —O— 2,6-diMeO- phenyl  911 —CH₂— pyridin-2,6-diyl —O— 3,4-diMeO- phenyl  912 —CH₂— pyridin-2,6-diyl —O— 3,5-diMeO- phenyl  913 —CH₂— pyridin-2,6-diyl —O— cyclopropyl  914 —CH₂— pyridin-2,6-diyl —O— cyclobutyl  915 —CH₂— pyridin-2,6-diyl —O— cyclopentyl  916 —CH₂— pyridin-2,6-diyl —O— cyclohexyl  917 —CH₂— pyridin-2,6-diyl —O— 2-furanyl  918 —CH₂— pyridin-2,6-diyl —O— 2-thienyl  919 —CH₂— pyridin-2,6-diyl CH₂CH₂ 2-imidazolyl  920 —CH₂— pyridin-2,6-diyl —O— 2-pyridyl  921 —CH₂— pyridin-2,6-diyl —O— 3-pyridyl  922 —CH₂— pyridin-2,6-diyl —O— 4-pyridyl  923 —CH₂— pyridin-2,6-diyl CH₂CH₂ N-morpholinyl  924 —CH₂— pyridin-2,6-diyl CH₂CH₂ N-piperidinyl  925 —CH₂— pyridin-2,6-diyl —O— 3-Me-2-pyridyl  926 —CH₂— pyridin-2,6-diyl —O— 4-Me-2-pyridyl  927 —CH₂— pyridin-2,6-diyl CH₂CH₂ 1-indolyl  928 —CH₂— pyridin-2,6-diyl —O— 2-benzothienyl  929 —CH₂— pyridin-2,6-diyl —O— 2-benzofuranyl  930 —CH₂— pyridin-2,6-diyl CH₂CH₂ 1-benzimidazole  931 —CH₂— pyridin-2,6-diyl —O— 2-naphthyl  932 —CH₂— pyridin-2,4-diyl —O— phenyl  933 —CH₂— pyridin-2,4-diyl —O— 3,3- diphenylmethyl  934 —CH₂— pyridin-2,4-diyl —O— 2-F-phenyl  935 —CH₂— pyridin-2,4-diyl —O— 3-F-phenyl  936 —CH₂— pyridin-2,4-diyl —O— 4-F-phenyl  937 —CH₂— pyridin-2,4-diyl —O— 2-Cl-phenyl  938 —CH₂— pyridin-2,4-diyl —O— 3-Cl-phenyl  939 —CH₂— pyridin-2,4-diyl —O— 4-Cl-phenyl  940 —CH₂— pyridin-2,4-diyl —O— 2-Me-phenyl  941 —CH₂— pyridin-2,4-diyl —O— 3-Me-phenyl  942 —CH₂— pyridin-2,4-diyl —O— 4-Me-phenyl  943 —CH₂— pyridin-2,4-diyl —O— 2-MeO-phenyl  944 —CH₂— pyridin-2,4-diyl —O— 3-MeO-phenyl  945 —CH₂— pyridin-2,4-diyl —O— 4-MeO-phenyl  946 —CH₂— pyridin-2,4-diyl —O— 2-MeS-phenyl  947 —CH₂— pyridin-2,4-diyl —O— 3-MeS-phenyl  948 —CH₂— pyridin-2,4-diyl —O— 4-MeS-phenyl  949 —CH₂— pyridin-2,4-diyl —O— 2-F₃C-phenyl  950 —CH₂— pyridin-2,4-diyl —O— 3-F₃C-phenyl  951 —CH₂— pyridin-2,4-diyl —O— 4-F₃C-phenyl  952 —CH₂— pyridin-2,4-diyl —O— 2,3-diF-phenyl  953 —CH₂— pyridin-2,4-diyl —O— 2,4-diF-phenyl  954 —CH₂— pyridin-2,4-diyl —O— 2,5-diF-phenyl  955 —CH₂— pyridin-2,4-diyl —O— 2,6-diF-phenyl  956 —CH₂— pyridin-2,4-diyl —O— 3,4-diF-phenyl  957 —CH₂— pyridin-2,4-diyl —O— 3,5-diF-phenyl  958 —CH₂— pyridin-2,4-diyl —O— 2,3-diCl-phenyl  959 —CH₂— pyridin-2,4-diyl —O— 2,4-diCl-phenyl  960 —CH₂— pyridin-2,4-diyl —O— 2,5-diCl-phenyl  961 —CH₂— pyridin-2,4-diyl —O— 2,6-diCl-phenyl  962 —CH₂— pyridin-2,4-diyl —O— 3,4-diCl-phenyl  963 —CH₂— pyridin-2,4-diyl —O— 3,5-diCl-phenyl  964 —CH₂— pyridin-2,4-diyl —O— 2-Cl-3-F-phenyl  965 —CH₂— pyridin-2,4-diyl —O— 2-Cl-4-F-phenyl  966 —CH₂— pyridin-2,4-diyl —O— 2-Cl-5-F-phenyl  967 —CH₂— pyridin-2,4-diyl —O— 3-Cl-4-F-phenyl  968 —CH₂— pyridin-2,4-diyl —O— 3-Cl-5-F-phenyl  969 —CH₂— pyridin-2,4-diyl —O— 4-Cl-2-F-phenyl  970 —CH₂— pyridin-2,4-diyl —O— 4-Cl-3-F-phenyl  971 —CH₂— pyridin-2,4-diyl —O— 2,3-diMeO- phenyl  972 —CH₂— pyridin-2,4-diyl —O— 2,4-diMeO- phenyl  973 —CH₂— pyridin-2,4-diyl —O— 2,5-diMeO- phenyl  974 —CH₂— pyridin-2,4-diyl —O— 2,6-diMeO- phenyl  975 —CH₂— pyridin-2,4-diyl —O— 3,4-diMeO- phenyl  976 —CH₂— pyridin-2,4-diyl —O— 3,5-diMeO- phenyl  977 —CH₂— pyridin-2,4-diyl —O— cyclopropyl  978 —CH₂— pyridin-2,4-diyl —O— cyclobutyl  979 —CH₂— pyridin-2,4-diyl —O— cyclopentyl  980 —CH₂— pyridin-2,4-diyl —O— cyclohexyl  981 —CH₂— pyridin-2,4-diyl —O— 2-furanyl  982 —CH₂— pyridin-2,4-diyl —O— 2-thienyl  983 —CH₂— pyridin-2,4-diyl CH₂CH₂ 2-imidazolyl  984 —CH₂— pyridin-2,4-diyl —O— 2-pyridyl  985 —CH₂— pyridin-2,4-diyl —O— 3-pyridyl  986 —CH₂— pyridin-2,4-diyl —O— 4-pyridyl  987 —CH₂— pyridin-2,4-diyl CH₂CH₂ N-morpholinyl  988 —CH₂— pyridin-2,4-diyl CH₂CH₂ N-piperidinyl  989 —CH₂— pyridin-2,4-diyl —O— 3-Me-2-pyridyl  990 —CH₂— pyridin-2,4-diyl —O— 4-Me-2-pyridyl  991 —CH₂— pyridin-2,4-diyl CH₂CH₂ 1-indolyl  992 —CH₂— pyridin-2,4-diyl —O— 2-benzothienyl  993 —CH₂— pyridin-2,4-diyl —O— 2-benzofuranyl  994 —CH₂— pyridin-2,4-diyl CH₂CH₂ 1-benzimidazole  995 —CH₂— pyridin-2,4-diyl —O— 2-naphthyl  996 —CH₂— pyridin-4,2-diyl —O— phenyl  997 —CH₂— pyridin-4,2-diyl —O— 3,3- diphenylmethyl  998 —CH₂— pyridin-4,2-diyl —O— 2-F-phenyl  999 —CH₂— pyridin-4,2-diyl —O— 3-F-phenyl 1000 —CH₂— pyridin-4,2-diyl —O— 4-F-phenyl 1001 —CH₂— pyridin-4,2-diyl —O— 2-Cl-phenyl 1002 —CH₂— pyridin-4,2-diyl —O— 3-Cl-phenyl 1003 —CH₂— pyridin-4,2-diyl —O— 4-Cl-phenyl 1004 —CH₂— pyridin-4,2-diyl —O— 2-Me-phenyl 1005 —CH₂— pyridin-4,2-diyl —O— 3-Me-phenyl 1006 —CH₂— pyridin-4,2-diyl —O— 4-Me-phenyl 1007 —CH₂— pyridin-4,2-diyl —O— 2-MeO-phenyl 1008 —CH₂— pyridin-4,2-diyl —O— 3-MeO-phenyl 1009 —CH₂— pyridin-4,2-diyl —O— 4-MeO-phenyl 1010 —CH₂— pyridin-4,2-diyl —O— 2-MeS-phenyl 1011 —CH₂— pyridin-4,2-diyl —O— 3-MeS-phenyl 1012 —CH₂— pyridin-4,2-diyl —O— 4-MeS-phenyl 1013 —CH₂— pyridin-4,2-diyl —O— 2-F₃C-phenyl 1014 —CH₂— pyridin-4,2-diyl —O— 3-F₃C-phenyl 1015 —CH₂— pyridin-4,2-diyl —O— 4-F₃C-phenyl 1016 —CH₂— pyridin-4,2-diyl —O— 2,3-diF-phenyl 1017 —CH₂— pyridin-4,2-diyl —O— 2,4-diF-phenyl 1018 —CH₂— pyridin-4,2-diyl —O— 2,5-diF-phenyl 1019 —CH₂— pyridin-4,2-diyl —O— 2,6-diF-phenyl 1020 —CH₂— pyridin-4,2-diyl —O— 3,4-diF-phenyl 1021 —CH₂— pyridin-4,2-diyl —O— 3,5-diF-phenyl 1022 —CH₂— pyridin-4,2-diyl —O— 2,3-diCl-phenyl 1023 —CH₂— pyridin-4,2-diyl —O— 2,4-diCl-phenyl 1024 —CH₂— pyridin-4,2-diyl —O— 2,5-diCl-phenyl 1025 —CH₂— pyridin-4,2-diyl —O— 2,6-diCl-phenyl 1026 —CH₂— pyridin-4,2-diyl —O— 3,4-diCl-phenyl 1027 —CH₂— pyridin-4,2-diyl —O— 3,5-diCl-phenyl 1028 —CH₂— pyridin-4,2-diyl —O— 2-Cl-3-F-phenyl 1029 —CH₂— pyridin-4,2-diyl —O— 2-Cl-4-F-phenyl 1030 —CH₂— pyridin-4,2-diyl —O— 2-Cl-5-F-phenyl 1031 —CH₂— pyridin-4,2-diyl —O— 3-Cl-4-F-phenyl 1032 —CH₂— pyridin-4,2-diyl —O— 3-Cl-5-F-phenyl 1033 —CH₂— pyridin-4,2-diyl —O— 4-Cl-2-F-phenyl 1034 —CH₂— pyridin-4,2-diyl —O— 4-Cl-3-F-phenyl 1035 —CH₂— pyridin-4,2-diyl —O— 2,3-diMeO- phenyl 1036 —CH₂— pyridin-4,2-diyl —O— 2,4-diMeO- phenyl 1037 —CH₂— pyridin-4,2-diyl —O— 2,5-diMeO- phenyl 1038 —CH₂— pyridin-4,2-diyl —O— 2,6-diMeO- phenyl 1039 —CH₂— pyridin-4,2-diyl —O— 3,4-diMeO- phenyl 1040 —CH₂— pyridin-4,2-diyl —O— 3,5-diMeO- phenyl 1041 —CH₂— pyridin-4,2-diyl —O— cyclopropyl 1042 —CH₂— pyridin-4,2-diyl —O— cyclobutyl 1043 —CH₂— pyridin-4,2-diyl —O— cyclopentyl 1044 —CH₂— pyridin-4,2-diyl —O— cyclohexyl 1045 —CH₂— pyridin-4,2-diyl —O— 2-furanyl 1046 —CH₂— pyridin-4,2-diyl —O— 2-thienyl 1047 —CH₂— pyridin-4,2-diyl CH₂CH₂ 2-imidazolyl 1048 —CH₂— pyridin-4,2-diyl —O— 2-pyridyl 1049 —CH₂— pyridin-4,2-diyl —O— 3-pyridyl 1050 —CH₂— pyridin-4,2-diyl —O— 4-pyridyl 1051 —CH₂— pyridin-4,2-diyl CH₂CH₂ N-morpholinyl 1052 —CH₂— pyridin-4,2-diyl CH₂CH₂ N-piperidinyl 1053 —CH₂— pyridin-4,2-diyl —O— 3-Me-2-pyridyl 1054 —CH₂— pyridin-4,2-diyl —O— 4-Me-2-pyridyl 1055 —CH₂— pyridin-4,2-diyl CH₂CH₂ 1-indolyl 1056 —CH₂— pyridin-4,2-diyl —O— 2-benzothienyl 1057 —CH₂— pyridin-4,2-diyl —O— 2-benzofuranyl 1058 —CH₂— pyridin-4,2-diyl CH₂CH₂ 1-benzimidazole 1059 —CH₂— pyridin-4,2-diyl —O— 2-naphthyl 1060 —CH₂— piperidin-1,3- —O— phenyl diyl 1061 —CH₂— piperidin-1,3- —O— 3,3- diyl diphenylmethyl 1062 —CH₂— piperidin-1,3- —O— 2-F-phenyl diyl 1063 —CH₂— piperidin-1,3- —O— 3-F-phenyl diyl 1064 —CH₂— piperidin-1,3- —O— 4-F-phenyl diyl 1065 —CH₂— piperidin-1,3- —O— 2-Cl-phenyl diyl 1066 —CH₂— piperidin-1,3- —O— 3-Cl-phenyl diyl 1067 —CH₂— piperidin-1,3- —O— 4-Cl-phenyl diyl 1068 —CH₂— piperidin-1,3- —O— 2-Me-phenyl diyl 1069 —CH₂— piperidin-1,3- —O— 3-Me-phenyl diyl 1070 —CH₂— piperidin-1,3- —O— 4-Me-phenyl diyl 1071 —CH₂— piperidin-1,3- —O— 2-MeO-phenyl diyl 1072 —CH₂— piperidin-1,3- —O— 3-MeO-phenyl diyl 1073 —CH₂— piperidin-1,3- —O— 4-MeO-phenyl diyl 1074 —CH₂— piperidin-1,3- —O— 2-MeS-phenyl diyl 1075 —CH₂— piperidin-1,3- —O— 3-MeS-phenyl diyl 1076 —CH₂— piperidin-1,3- —O— 4-MeS-phenyl diyl 1077 —CH₂— piperidin-1,3- —O— 2-F₃C-phenyl diyl 1078 —CH₂— piperidin-1,3- —O— 3-F₃C-phenyl diyl 1079 —CH₂— piperidin-1,3- —O— 4-F₃C-phenyl diyl 1080 —CH₂— piperidin-1,3- —O— 2,3-diF-phenyl diyl 1081 —CH₂— piperidin-1,3- —O— 2,4-diF-phenyl diyl 1082 —CH₂— piperidin-1,3- —O— 2,5-diF-phenyl diyl 1083 —CH₂— piperidin-1,3- —O— 2,6-diF-phenyl diyl 1084 —CH₂— piperidin-1,3- —O— 3,4-diF-phenyl diyl 1085 —CH₂— piperidin-1,3- —O— 3,5-diF-phenyl diyl 1086 —CH₂— piperidin-1,3- —O— 2,3-diCl-phenyl diyl 1087 —CH₂— piperidin-1,3- —O— 2,4-diCl-phenyl diyl 1088 —CH₂— piperidin-1,3- —O— 2,5-diCl-phenyl diyl 1089 —CH₂— piperidin-1,3- —O— 2,6-diCl-phenyl diyl 1090 —CH₂— piperidin-1,3- —O— 3,4-diCl-phenyl diyl 1091 —CH₂— piperidin-1,3- —O— 3,5-diCl-phenyl diyl 1092 —CH₂— piperidin-1,3- —O— 2-Cl-3-F-phenyl diyl 1093 —CH₂— piperidin-1,3- —O— 2-Cl-4-F-phenyl diyl 1094 —CH₂— piperidin-1,3- —O— 2-Cl-5-F-phenyl diyl 1095 —CH₂— piperidin-1,3- —O— 3-Cl-4-F-phenyl diyl 1096 —CH₂— piperidin-1,3- —O— 3-Cl-5-F-phenyl diyl 1097 —CH₂— piperidin-1,3- —O— 4-Cl-2-F-phenyl diyl 1098 —CH₂— piperidin-1,3- —O— 4-Cl-3-F-phenyl diyl 1099 —CH₂— piperidin-1,3- —O— 2,3-diMeO- diyl phenyl 1100 —CH₂— piperidin-1,3- —O— 2,4-diMeO- diyl phenyl 1101 —CH₂— piperidin-1,3- —O— 2,5-diMeO- diyl phenyl 1102 —CH₂— piperidin-1,3- —O— 2,6-diMeO- diyl phenyl 1103 —CH₂— piperidin-1,3- —O— 3,4-diMeO- diyl phenyl 1104 —CH₂— piperidin-1,3- —O— 3,5-diMeO- diyl phenyl 1105 —CH₂— piperidin-1,3- —O— Cyclopropyl diyl 1106 —CH₂— piperidin-1,3- —O— Cyclobutyl diyl 1107 —CH₂— piperidin-1,3- —O— Cyclopentyl diyl 1108 —CH₂— piperidin-1,3- —O— Cyclohexyl diyl 1109 —CH₂— piperidin-1,3- —O— 2-furanyl diyl 1110 —CH₂— piperidin-1,3- —O— 2-thienyl diyl 1111 —CH₂— piperidin-1,3- CH₂CH₂ 2-imidazolyl diyl 1112 —CH₂— piperidin-1,3- —O— 2-pyridyl diyl 1113 —CH₂— piperidin-1,3- —O— 3-pyridyl diyl 1114 —CH₂— piperidin-1,3- —O— 4-pyridyl diyl 1115 —CH₂— piperidin-1,3- CH₂CH₂ N-morpholinyl diyl 1116 —CH₂— piperidin-1,3- CH₂CH₂ N-piperidinyl diyl 1117 —CH₂— piperidin-1,3- —O— 3-Me-2-pyridyl diyl 1118 —CH₂— piperidin-1,3- —O— 4-Me-2-pyridyl diyl 1119 —CH₂— piperidin-1,3- CH₂CH₂ 1-indolyl diyl 1120 —CH₂— piperidin-1,3- —O— 2-benzothienyl diyl 1121 —CH₂— piperidin-1,3- —O— 2-benzofuranyl diyl 1122 —CH₂— piperidin-1,3- CH₂CH₂ 1-benzimidazole diyl 1123 —CH₂— piperidin-1,3- —O— 2-naphthyl diyl 1124 —CH₂— piperidin-3,1- —O— Phenyl diyl 1125 —CH₂— piperidin-3,1- —O— 3,3- diyl diphenylmethyl 1126 —CH₂— piperidin-3,1- —O— 2-F-phenyl diyl 1127 —CH₂— piperidin-3,1- —O— 3-F-phenyl diyl 1128 —CH₂— piperidin-3,1- —O— 4-F-phenyl diyl 1129 —CH₂— piperidin-3,1- —O— 2-Cl-phenyl diyl 1130 —CH₂— piperidin-3,1- —O— 3-Cl-phenyl diyl 1131 —CH₂— piperidin-3,1- —O— 4-Cl-phenyl diyl 1132 —CH₂— piperidin-3,1- —O— 2-Me-phenyl diyl 1133 —CH₂— piperidin-3,1- —O— 3-Me-phenyl diyl 1134 —CH₂— piperidin-3,1- —O— 4-Me-phenyl diyl 1135 —CH₂— piperidin-3,1- —O— 2-MeO-phenyl diyl 1136 —CH₂— piperidin-3,1- —O— 3-MeO-phenyl diyl 1137 —CH₂— piperidin-3,1- —O— 4-MeO-phenyl diyl 1138 —CH₂— piperidin-3,1- —O— 2-MeS-phenyl diyl 1139 —CH₂— piperidin-3,1- —O— 3-MeS-phenyl diyl 1140 —CH₂— piperidin-3,1- —O— 4-MeS-phenyl diyl 1141 —CH₂— piperidin-3,1- —O— 2-F₃C-phenyl diyl 1142 —CH₂— piperidin-3,1- —O— 3-F₃C-phenyl diyl 1143 —CH₂— piperidin-3,1- —O— 4-F₃C-phenyl diyl 1144 —CH₂— piperidin-3,1- —O— 2,3-diF-phenyl diyl 1145 —CH₂— piperidin-3,1- —O— 2,4-diF-phenyl diyl 1146 —CH₂— piperidin-3,1- —O— 2,5-diF-phenyl diyl 1147 —CH₂— piperidin-3,1- —O— 2,6-diF-phenyl diyl 1148 —CH₂— piperidin-3,1- —O— 3,4-diF-phenyl diyl 1149 —CH₂— piperidin-3,1- —O— 3,5-diF-phenyl diyl 1150 —CH₂— piperidin-3,1- —O— 2,3-diCl-phenyl diyl 1151 —CH₂— piperidin-3,1- —O— 2,4-diCl-phenyl diyl 1152 —CH₂— piperidin-3,1- —O— 2,5-diCl-phenyl diyl 1153 —CH₂— piperidin-3,1- —O— 2,6-diCl-phenyl diyl 1154 —CH₂— piperidin-3,1- —O— 3,4-diCl-phenyl diyl 1155 —CH₂— piperidin-3,1- —O— 3,5-diCl-phenyl diyl 1156 —CH₂— piperidin-3,1- —O— 2-Cl-3-F-phenyl diyl 1157 —CH₂— piperidin-3,1- —O— 2-Cl-4-F-phenyl diyl 1158 —CH₂— piperidin-3,1- —O— 2-Cl-5-F-phenyl diyl 1159 —CH₂— piperidin-3,1- —O— 3-Cl-4-F-phenyl diyl 1160 —CH₂— piperidin-3,1- —O— 3-Cl-5-F-phenyl diyl 1161 —CH₂— piperidin-3,1- —O— 4-Cl-2-F-phenyl diyl 1162 —CH₂— piperidin-3,1- —O— 4-Cl-3-F-phenyl diyl 1163 —CH₂— piperidin-3,1- —O— 2,3-diMeO- diyl phenyl 1164 —CH₂— piperidin-3,1- —O— 2,4-diMeO- diyl phenyl 1165 —CH₂— piperidin-3,1- —O— 2,5-diMeO- diyl phenyl 1166 —CH₂— piperidin-3,1- —O— 2,6-diMeO- diyl phenyl 1167 —CH₂— piperidin-3,1- —O— 3,4-diMeO- diyl phenyl 1168 —CH₂— piperidin-3,1- —O— 3,5-diMeO- diyl phenyl 1169 —CH₂— piperidin-3,1- —O— Cyclopropyl diyl 1170 —CH₂— piperidin-3,1- —O— Cyclobutyl diyl 1171 —CH₂— piperidin-3,1- —O— Cyclopentyl diyl 1172 —CH₂— piperidin-3,1- —O— Cyclohexyl diyl 1173 —CH₂— piperidin-3,1- —O— 2-furanyl diyl 1174 —CH₂— piperidin-3,1- —O— 2-thienyl diyl 1175 —CH₂— piperidin-3,1- CH₂CH₂ 2-imidazolyl diyl 1176 —CH₂— piperidin-3,1- —O— 2-pyridyl diyl 1177 —CH₂— piperidin-3,1- —O— 3-pyridyl diyl 1178 —CH₂— piperidin-3,1- —O— 4-pyridyl diyl 1179 —CH₂— piperidin-3,1- CH₂CH₂ N-morpholinyl diyl 1180 —CH₂— piperidin-3,1- CH₂CH₂ N-piperidinyl diyl 1181 —CH₂— piperidin-3,1- —O— 3-Me-2-pyridyl diyl 1182 —CH₂— piperidin-3,1- —O— 4-Me-2-pyridyl diyl 1183 —CH₂— piperidin-3,1- CH₂CH₂ 1-indolyl diyl 1184 —CH₂— piperidin-3,1- —O— 2-benzothienyl diyl 1185 —CH₂— piperidin-3,1- —O— 2-benzofuranyl diyl 1186 —CH₂— piperidin-3,1- CH₂CH₂ 1-benzimidazole diyl 1187 —CH₂— piperidin-3,1- —O— 2-naphthyl diyl 1188 —CH₂— cyclohex-1,3- —O— Phenyl diyl 1189 —CH₂— cyclohex-1,3- —O— 3,3- diyl diphenylmethyl 1190 —CH₂— cyclohex-1,3- —O— 2-F-phenyl diyl 1191 —CH₂— cyclohex-1,3- —O— 3-F-phenyl diyl 1192 —CH₂— cyclohex-1,3- —O— 4-F-phenyl diyl 1193 —CH₂— cyclohex-1,3- —O— 2-Cl-phenyl diyl 1194 —CH₂— cyclohex-1,3- —O— 3-Cl-phenyl diyl 1195 —CH₂— cyclohex-1,3- —O— 4-Cl-phenyl diyl 1196 —CH₂— cyclohex-1,3- —O— 2-Me-phenyl diyl 1197 —CH₂— cyclohex-1,3- —O— 3-Me-phenyl diyl 1198 —CH₂— cyclohex-1,3- —O— 4-Me-phenyl diyl 1199 —CH₂— cyclohex-1,3- —O— 2-MeO-phenyl diyl 1200 —CH₂— cyclohex-1,3- —O— 3-MeO-phenyl diyl 1201 —CH₂— cyclohex-1,3- —O— 4-MeO-phenyl diyl 1202 —CH₂— cyclohex-1,3- —O— 2-MeS-phenyl diyl 1203 —CH₂— cyclohex-1,3- —O— 3-MeS-phenyl diyl 1204 —CH₂— cyclohex-1,3- —O— 4-MeS-phenyl diyl 1205 —CH₂— cyclohex-1,3- —O— 2-F₃C-phenyl diyl 1206 —CH₂— cyclohex-1,3- —O— 3-F₃C-phenyl diyl 1207 —CH₂— cyclohex-1,3- —O— 4-F₃C-phenyl diyl 1208 —CH₂— cyclohex-1,3- —O— 2,3-diF-phenyl diyl 1209 —CH₂— cyclohex-1,3- —O— 2,4-diF-phenyl diyl 1210 —CH₂— cyclohex-1,3- —O— 2,5-diF-phenyl diyl 1211 —CH₂— cyclohex-1,3- —O— 2,6-diF-phenyl diyl 1212 —CH₂— cyclohex-1,3- —O— 3,4-diF-phenyl diyl 1213 —CH₂— cyclohex-1,3- —O— 3,5-diF-phenyl diyl 1214 —CH₂— cyclohex-1,3- —O— 2,3-diCl-phenyl diyl 1215 —CH₂— cyclohex-1,3- —O— 2,4-diCl-phenyl diyl 1216 —CH₂— cyclohex-1,3- —O— 2,5-diCl-phenyl diyl 1217 —CH₂— cyclohex-1,3- —O— 2,6-diCl-phenyl diyl 1218 —CH₂— cyclohex-1,3- —O— 3,4-diCl-phenyl diyl 1219 —CH₂— cyclohex-1,3- —O— 3,5-diCl-phenyl diyl 1220 —CH₂— cyclohex-1,3- —O— 2-Cl-3-F-phenyl diyl 1221 —CH₂— cyclohex-1,3- —O— 2-Cl-4-F-phenyl diyl 1222 —CH₂— cyclohex-1,3- —O— 2-Cl-5-F-phenyl diyl 1223 —CH₂— cyclohex-1,3- —O— 3-Cl-4-F-phenyl diyl 1224 —CH₂— cyclohex-1,3- —O— 3-Cl-5-F-phenyl diyl 1225 —CH₂— cyclohex-1,3- —O— 4-Cl-2-F-phenyl diyl 1226 —CH₂— cyclohex-1,3- —O— 4-Cl-3-F-phenyl diyl 1227 —CH₂— cyclohex-1,3- —O— 2,3-diMeO- diyl phenyl 1228 —CH₂— cyclohex-1,3- —O— 2,4-diMeO- diyl phenyl 1229 —CH₂— cyclohex-1,3- —O— 2,5-diMeO- diyl phenyl 1230 —CH₂— cyclohex-1,3- —O— 2,6-diMeO- diyl phenyl 1231 —CH₂— cyclohex-1,3- —O— 3,4-diMeO- diyl phenyl 1232 —CH₂— cyclohex-1,3- —O— 3,5-diMeO- diyl phenyl 1233 —CH₂— cyclohex-1,3- —O— Cyclopropyl diyl 1234 —CH₂— cyclohex-1,3- —O— Cyclobutyl diyl 1235 —CH₂— cyclohex-1,3- —O— Cyclopentyl diyl 1236 —CH₂— cyclohex-1,3- —O— Cyclohexyl diyl 1237 —CH₂— cyclohex-1,3- —O— 2-furanyl diyl 1238 —CH₂— cyclohex-1,3- —O— 2-thienyl diyl 1239 —CH₂— cyclohex-1,3- CH₂CH₂ 2-imidazolyl diyl 1240 —CH₂— cyclohex-1,3- —O— 2-pyridyl diyl 1241 —CH₂— cyclohex-1,3- —O— 3-pyridyl diyl 1242 —CH₂— cyclohex-1,3- —O— 4-pyridyl diyl 1243 —CH₂— cyclohex-1,3- CH₂CH₂ N-morpholinyl diyl 1244 —CH₂— cyclohex-1,3- CH₂CH₂ N-piperidinyl diyl 1245 —CH₂— cyclohex-1,3- —O— 3-Me-2-pyridyl diyl 1246 —CH₂— cyclohex-1,3- —O— 4-Me-2-pyridyl diyl 1247 —CH₂— cyclohex-1,3- CH₂CH₂ 1-indolyl diyl 1248 —CH₂— cyclohex-1,3- —O— 2-benzothienyl diyl 1249 —CH₂— cyclohex-1,3- —O— 2-benzofuranyl diyl 1250 —CH₂— cyclohex-1,3- CH₂CH₂ 1-benzimidazole diyl 1251 —CH₂— cyclohex-1,3- —O— 2-naphthyl diyl 1252 —CH₂— cyclopropan- —O— Phenyl 1,2-diyl 1253 —CH₂— cyclopropan- —O— 3,3- 1,2-diyl diphenylmethyl 1254 —CH₂— cyclopropan- —O— 2-F-phenyl 1,2-diyl 1255 —CH₂— cyclopropan- —O— 3-F-phenyl 1,2-diyl 1256 —CH₂— cyclopropan- —O— 4-F-phenyl 1,2-diyl 1257 —CH₂— cyclopropan- —O— 2-Cl-phenyl 1,2-diyl 1258 —CH₂— cyclopropan- —O— 3-Cl-phenyl 1,2-diyl 1259 —CH₂— cyclopropan- —O— 4-Cl-phenyl 1,2-diyl 1260 —CH₂— cyclopropan- —O— 2-Me-phenyl 1,2-diyl 1261 —CH₂— cyclopropan- —O— 3-Me-phenyl 1,2-diyl 1262 —CH₂— cyclopropan- —O— 4-Me-phenyl 1,2-diyl 1263 —CH₂— cyclopropan- —O— 2-MeO-phenyl 1,2-diyl 1264 —CH₂— cyclopropan- —O— 3-MeO-phenyl 1,2-diyl 1265 —CH₂— cyclopropan- —O— 4-MeO-phenyl 1,2-diyl 1266 —CH₂— cyclopropan- —O— 2-MeS-phenyl 1,2-diyl 1267 —CH₂— cyclopropan- —O— 3-MeS-phenyl 1,2-diyl 1268 —CH₂— cyclopropan- —O— 4-MeS-phenyl 1,2-diyl 1269 —CH₂— cyclopropan- —O— 2-F₃C-phenyl 1,2-diyl 1270 —CH₂— cyclopropan- —O— 3-F₃C-phenyl 1,2-diyl 1271 —CH₂— cyclopropan- —O— 4-F₃C-phenyl 1,2-diyl 1272 —CH₂— cyclopropan- —O— 2,3-diF-phenyl 1,2-diyl 1273 —CH₂— cyclopropan- —O— 2,4-diF-phenyl 1,2-diyl 1274 —CH₂— cyclopropan- —O— 2,5-diF-phenyl 1,2-diyl 1275 —CH₂— cyclopropan- —O— 2,6-diF-phenyl 1,2-diyl 1276 —CH₂— cyclopropan- —O— 3,4-diF-phenyl 1,2-diyl 1277 —CH₂— cyclopropan- —O— 3,5-diF-phenyl 1,2-diyl 1278 —CH₂— cyclopropan- —O— 2,3-diCl-phenyl 1,2-diyl 1279 —CH₂— cyclopropan- —O— 2,4-diCl-phenyl 1,2-diyl 1280 —CH₂— cyclopropan- —O— 2,5-diCl-phenyl 1,2-diyl 1281 —CH₂— cyclopropan- —O— 2,6-diCl-phenyl 1,2-diyl 1282 —CH₂— cyclopropan- —O— 3,4-diCl-phenyl 1,2-diyl 1283 —CH₂— cyclopropan- —O— 3,5-diCl-phenyl 1,2-diyl 1284 —CH₂— cyclopropan- —O— 2-Cl-3-F-phenyl 1,2-diyl 1285 —CH₂— cyclopropan- —O— 2-Cl-4-F-phenyl 1,2-diyl 1286 —CH₂— cyclopropan- —O— 2-Cl-5-F-phenyl 1,2-diyl 1287 —CH₂— cyclopropan- —O— 3-Cl-4-F-phenyl 1,2-diyl 1288 —CH₂— cyclopropan- —O— 3-Cl-5-F-phenyl 1,2-diyl 1289 —CH₂— cyclopropan- —O— 4-Cl-2-F-phenyl 1,2-diyl 1290 —CH₂— cyclopropan- —O— 4-Cl-3-F-phenyl 1,2-diyl 1291 —CH₂— cyclopropan- —O— 2,3-diMeO- 1,2-diyl phenyl 1292 —CH₂— cyclopropan- —O— 2,4-diMeO- 1,2-diyl phenyl 1293 —CH₂— cyclopropan- —O— 2,5-diMeO- 1,2-diyl phenyl 1294 —CH₂— cyclopropan- —O— 2,6-diMeO- 1,2-diyl phenyl 1295 —CH₂— cyclopropan- —O— 3,4-diMeO- 1,2-diyl phenyl 1296 —CH₂— cyclopropan- —O— 3,5-diMeO- 1,2-diyl phenyl 1297 —CH₂— cyclopropan- —O— Cyclopropyl 1,2-diyl 1298 —CH₂— cyclopropan- —O— Cyclobutyl 1,2-diyl 1299 —CH₂— cyclopropan- —O— Cyclopentyl 1,2-diyl 1300 —CH₂— cyclopropan- —O— Cyclohexyl 1,2-diyl 1301 —CH₂— cyclopropan- —O— 2-furanyl 1,2-diyl 1302 —CH₂— cyclopropan- —O— 2-thienyl 1,2-diyl 1303 —CH₂— cyclopropan- CH₂CH₂ 2-imidazolyl 1,2-diyl 1304 —CH₂— cyclopropan- —O— 2-pyridyl 1,2-diyl 1305 —CH₂— cyclopropan- —O— 3-pyridyl 1,2-diyl 1306 —CH₂— cyclopropan- —O— 4-pyridyl 1,2-diyl 1307 —CH₂— cyclopropan- CH₂CH₂ N-morpholinyl 1,2-diyl 1308 —CH₂— cyclopropan- CH₂CH₂ N-piperidinyl 1,2-diyl 1309 —CH₂— cyclopropan- —O— 3-Me-2-pyridyl 1,2-diyl 1310 —CH₂— cyclopropan- —O— 4-Me-2-pyridyl 1,2-diyl 1311 —CH₂— cyclopropan- CH₂CH₂ 1-indolyl 1,2-diyl 1312 —CH₂— cyclopropan- —O— 2-benzothienyl 1,2-diyl 1313 —CH₂— cyclopropan- —O— 2-benzofuranyl 1,2-diyl 1314 —CH₂— cyclopropan- CH₂CH₂ 1-benzimidazole 1,2-diyl 1315 —CH₂— cyclopentan- —O— 2-naphthyl 1,2-diyl 1316 —CH₂— cyclopentan- —O— Phenyl 1,3-diyl 1317 —CH₂— cyclopentan- —O— 3,3- 1,3-diyl diphenylmethyl 1318 —CH₂— cyclopentan- —O— 2-F-phenyl 1,3-diyl 1319 —CH₂— cyclopentan- —O— 3-F-phenyl 1,3-diyl 1320 —CH₂— cyclopentan- —O— 4-F-phenyl 1,3-diyl 1321 —CH₂— cyclopentan- —O— 2-Cl-phenyl 1,3-diyl 1322 —CH₂— cyclopentan- —O— 3-Cl-phenyl 1,3-diyl 1323 —CH₂— cyclopentan- —O— 4-Cl-phenyl 1,3-diyl 1324 —CH₂— cyclopentan- —O— 2-Me-phenyl 1,3-diyl 1325 —CH₂— cyclopentan- —O— 3-Me-phenyl 1,3-diyl 1326 —CH₂— cyclopentan- —O— 4-Me-phenyl 1,3-diyl 1327 —CH₂— cyclopentan- —O— 2-MeO-phenyl 1,3-diyl 1328 —CH₂— cyclopentan- —O— 3-MeO-phenyl 1,3-diyl 1329 —CH₂— cyclopentan- —O— 4-MeO-phenyl 1,3-diyl 1330 —CH₂— cyclopentan- —O— 2-MeS-phenyl 1,3-diyl 1331 —CH₂— cyclopentan- —O— 3-MeS-phenyl 1,3-diyl 1332 —CH₂— cyclopentan- —O— 4-MeS-phenyl 1,3-diyl 1333 —CH₂— cyclopentan- —O— 2-F₃C-phenyl 1,3-diyl 1334 —CH₂— cyclopentan- —O— 3-F₃C-phenyl 1,3-diyl 1335 —CH₂— cyclopentan- —O— 4-F₃C-phenyl 1,3-diyl 1336 —CH₂— cyclopentan- —O— 2,3-diF-phenyl 1,3-diyl 1337 —CH₂— cyclopentan- —O— 2,4-diF-phenyl 1,3-diyl 1338 —CH₂— cyclopentan- —O— 2,5-diF-phenyl 1,3-diyl 1339 —CH₂— cyclopentan- —O— 2,6-diF-phenyl 1,3-diyl 1340 —CH₂— cyclopentan- —O— 3,4-diF-phenyl 1,3-diyl 1341 —CH₂— cyclopentan- —O— 3,5-diF-phenyl 1,3-diyl 1342 —CH₂— cyclopentan- —O— 2,3-diCl-phenyl 1,3-diyl 1343 —CH₂— cyclopentan- —O— 2,4-diCl-phenyl 1,3-diyl 1344 —CH₂— cyclopentan- —O— 2,5-diCl-phenyl 1,3-diyl 1345 —CH₂— cyclopentan- —O— 2,6-diCl-phenyl 1,3-diyl 1346 —CH₂— cyclopentan- —O— 3,4-diCl-phenyl 1,3-diyl 1347 —CH₂— cyclopentan- —O— 3,5-diCl-phenyl 1,3-diyl 1348 —CH₂— cyclopentan- —O— 2-Cl-3-F-phenyl 1,3-diyl 1349 —CH₂— cyclopentan- —O— 2-Cl-4-F-phenyl 1,3-diyl 1350 —CH₂— cyclopentan- —O— 2-Cl-5-F-phenyl 1,3-diyl 1351 —CH₂— cyclopentan- —O— 3-Cl-4-F-phenyl 1,3-diyl 1352 —CH₂— cyclopentan- —O— 3-Cl-5-F-phenyl 1,3-diyl 1353 —CH₂— cyclopentan- —O— 4-Cl-2-F-phenyl 1,3-diyl 1354 —CH₂— cyclopentan- —O— 4-Cl-3-F-phenyl 1,3-diyl 1355 —CH₂— cyclopentan- —O— 2,3-diMeO- 1,3-diyl phenyl 1356 —CH₂— cyclopentan- —O— 2,4-diMeO- 1,3-diyl phenyl 1357 —CH₂— cyclopentan- —O— 2,5-diMeO- 1,3-diyl phenyl 1358 —CH₂— cyclopentan- —O— 2,6-diMeO- 1,3-diyl phenyl 1359 —CH₂— cyclopentan- —O— 3,4-diMeO- 1,3-diyl phenyl 1360 —CH₂— cyclopentan- —O— 3,5-diMeO- 1,3-diyl phenyl 1361 —CH₂— cyclopentan- —O— Cyclopropyl 1,3-diyl 1362 —CH₂— cyclopentan- —O— Cyclobutyl 1,3-diyl 1363 —CH₂— cyclopentan- —O— Cyclopentyl 1,3-diyl 1364 —CH₂— cyclopentan- —O— Cyclohexyl 1,3-diyl 1365 —CH₂— cyclopentan- —O— 2-furanyl 1,3-diyl 1366 —CH₂— cyclopentan- —O— 2-thienyl 1,3-diyl 1367 —CH₂— cyclopentan- CH₂CH₂ 2-imidazolyl 1,3-diyl 1368 —CH₂— cyclopentan- —O— 2-pyridyl 1,3-diyl 1369 —CH₂— cyclopentan- —O— 3-pyridyl 1,3-diyl 1370 —CH₂— cyclopentan- —O— 4-pyridyl 1,3-diyl 1371 —CH₂— cyclopentan- CH₂CH₂ N-morpholinyl 1,3-diyl 1372 —CH₂— cyclopentan- CH₂CH₂ N-piperidinyl 1,3-diyl 1373 —CH₂— cyclopentan- —O— 3-Me-2-pyridyl 1,3-diyl 1374 —CH₂— cyclopentan- —O— 4-Me-2-pyridyl 1,3-diyl 1375 —CH₂— cyclopentan- CH₂CH₂ 1-indolyl 1,3-diyl 1376 —CH₂— cyclopentan- —O— 2-benzothienyl 1,3-diyl 1377 —CH₂— cyclopentan- —O— 2-benzofuranyl 1,3-diyl 1378 —CH₂— cyclopentan- CH₂CH₂ 1-benzimidazole 1,3-diyl 1379 —CH₂— cyclopentan- —O— 2-naphthyl 1,3-diyl 1380 —CH₂— bond bond phenyl 1381 —CH₂— bond bond 3,3-diphenyl 1382 —CH₂— bond bond 2-F-phenyl 1383 —CH₂— bond bond 3-F-phenyl 1384 —CH₂— bond bond 4-F-phenyl 1385 —CH₂— bond bond 2-Cl-phenyl 1386 —CH₂— bond bond 3-Cl-phenyl 1387 —CH₂— bond bond 4-Cl-phenyl 1388 —CH₂— bond bond 2-Me-phenyl 1389 —CH₂— bond bond 3-Me-phenyl 1390 —CH₂— bond bond 4-Me-phenyl 1391 —CH₂— bond bond 2-MeO-phenyl 1392 —CH₂— bond bond 3-MeO-phenyl 1393 —CH₂— bond bond 4-MeO-phenyl 1394 —CH₂— bond bond 2-MeS-phenyl 1395 —CH₂— bond bond 3-MeS-phenyl 1396 —CH₂— bond bond 4-MeS-phenyl 1397 —CH₂— bond bond 2-F₃C-phenyl 1398 —CH₂— bond bond 3-F₃C-phenyl 1399 —CH₂— bond bond 4-F₃C-phenyl 1400 —CH₂— bond bond 2,3-diF-phenyl 1401 —CH₂— bond bond 2,4-diF-phenyl 1402 —CH₂— bond bond 2,5-diF-phenyl 1403 —CH₂— bond bond 2,6-diF-phenyl 1404 —CH₂— bond bond 3,4-diF-phenyl 1405 —CH₂— bond bond 3,5-diF-phenyl 1406 —CH₂— bond bond 2,3-diCl-phenyl 1407 —CH₂— bond bond 2,4-diCl-phenyl 1408 —CH₂— bond bond 2,5-diCl-phenyl 1409 —CH₂— bond bond 2,6-diCl-phenyl 1410 —CH₂— bond bond 3,4-diCl-phenyl 1411 —CH₂— bond bond 3,5-diCl-phenyl 1412 —CH₂— bond bond 2-Cl-3-F-phenyl 1413 —CH₂— bond bond 2-Cl-4-F-phenyl 1414 —CH₂— bond bond 2-Cl-5-F-phenyl 1415 —CH₂— bond bond 3-Cl-4-F-phenyl 1416 —CH₂— bond bond 3-Cl-5-F-phenyl 1417 —CH₂— bond bond 4-Cl-2-F-phenyl 1418 —CH₂— bond bond 4-Cl-3-F-phenyl 1419 —CH₂— bond bond 2,3-diMeO- phenyl 1420 —CH₂— bond bond 2,4-diMeO- phenyl 1421 —CH₂— bond bond 2,5-diMeO- phenyl 1422 —CH₂— bond bond 2,6-diMeO- phenyl 1423 —CH₂— bond bond 3,4-diMeO- phenyl 1424 —CH₂— bond bond 3,5-diMeO- phenyl 1425 —CH₂— bond bond cyclopropyl 1426 —CH₂— bond bond cyclobutyl 1427 —CH₂— bond bond cyclopentyl 1428 —CH₂— bond bond cyclohexyl 1429 —CH₂— bond bond 2-furanyl 1430 —CH₂— bond bond 2-thienyl 1431 —CH₂— bond bond 2-imidazolyl 1432 —CH₂— bond bond 2-pyridyl 1433 —CH₂— bond bond 3-pyridyl 1434 —CH₂— bond bond 4-pyridyl 1435 —CH₂— bond bond N-morpholinyl 1436 —CH₂— bond bond N-piperidinyl 1437 —CH₂— bond bond 3-Me-2-pyridyl 1438 —CH₂— bond bond 4-Me-2-pyridyl 1439 —CH₂— bond bond 1-indolyl 1440 —CH₂— bond bond 2-benzothienyl 1441 —CH₂— bond bond 2-benzofuranyl 1442 —CH₂— bond bond 1-benzimidazole 1443 —CH₂— bond bond 2-naphthyl 1444 —CH₂CH₂— bond bond phenyl 1445 —CH₂CH₂— bond bond 3,3-diphenyl 1446 —CH₂CH₂— bond bond 2-F-phenyl 1447 —CH₂CH₂— bond bond 3-F-phenyl 1448 —CH₂CH₂— bond bond 4-F-phenyl 1449 —CH₂CH₂— bond bond 2-Cl-phenyl 1450 —CH₂CH₂— bond bond 3-Cl-phenyl 1451 —CH₂CH₂— bond bond 4-Cl-phenyl 1452 —CH₂CH₂— bond bond 2-Me-phenyl 1453 —CH₂CH₂— bond bond 3-Me-phenyl 1454 —CH₂CH₂— bond bond 4-Me-phenyl 1455 —CH₂CH₂— bond bond 2-MeO-phenyl 1456 —CH₂CH₂— bond bond 3-MeO-phenyl 1457 —CH₂CH₂— bond bond 4-MeO-phenyl 1458 —CH₂CH₂— bond bond 2-MeS-phenyl 1459 —CH₂CH₂— bond bond 3-MeS-phenyl 1460 —CH₂CH₂— bond bond 4-MeS-phenyl 1461 —CH₂CH₂— bond bond 2-F₃C-phenyl 1462 —CH₂CH₂— bond bond 3-F₃C-phenyl 1463 —CH₂CH₂— bond bond 4-F₃C-phenyl 1464 —CH₂CH₂— bond bond 2,3-diF-phenyl 1465 —CH₂CH₂— bond bond 2,4-diF-phenyl 1466 —CH₂CH₂— bond bond 2,5-diF-phenyl 1467 —CH₂CH₂— bond bond 2,6-diF-phenyl 1468 —CH₂CH₂— bond bond 3,4-diF-phenyl 1469 —CH₂CH₂— bond bond 3,5-diF-phenyl 1470 —CH₂CH₂— bond bond 2,3-diCl-phenyl 1471 —CH₂CH₂— bond bond 2,4-diCl-phenyl 1472 —CH₂CH₂— bond bond 2,5-diCl-phenyl 1473 —CH₂CH₂— bond bond 2,6-diCl-phenyl 1474 —CH₂CH₂— bond bond 3,4-diCl-phenyl 1475 —CH₂CH₂— bond bond 3,5-diCl-phenyl 1476 —CH₂CH₂— bond bond 2-Cl-3-F-phenyl 1477 —CH₂CH₂— bond bond 2-Cl-4-F-phenyl 1478 —CH₂CH₂— bond bond 2-Cl-5-F-phenyl 1479 —CH₂CH₂— bond bond 3-Cl-4-F-phenyl 1480 —CH₂CH₂— bond bond 3-Cl-5-F-phenyl 1481 —CH₂CH₂— bond bond 4-Cl-2-F-phenyl 1482 —CH₂CH₂— bond bond 4-Cl-3-F-phenyl 1483 —CH₂CH₂— bond bond 2,3-diMeO- phenyl 1484 —CH₂CH₂— bond bond 2,4-diMeO- phenyl 1485 —CH₂CH₂— bond bond 2,5-diMeO- phenyl 1486 —CH₂CH₂— bond bond 2,6-diMeO- phenyl 1487 —CH₂CH₂— bond bond 3,4-diMeO- phenyl 1488 —CH₂CH₂— bond bond 3,5-diMeO- phenyl 1489 —CH₂CH₂— bond bond cyclopropyl 1490 —CH₂CH₂— bond bond cyclobutyl 1491 —CH₂CH₂— bond bond cyclopentyl 1492 —CH₂CH₂— bond bond cyclohexyl 1493 —CH₂CH₂— bond bond 2-furanyl 1494 —CH₂CH₂— bond bond 2-thienyl 1495 —CH₂CH₂— bond bond 2-imidazolyl 1496 —CH₂CH₂— bond bond 2-pyridyl 1497 —CH₂CH₂— bond bond 3-pyridyl 1498 —CH₂CH₂— bond bond 4-pyridyl 1499 —CH₂CH₂— bond bond N-morpholinyl 1500 —CH₂CH₂— bond bond N-piperidinyl 1501 —CH₂CH₂— bond bond 3-Me-2-pyridyl 1502 —CH₂CH₂— bond bond 4-Me-2-pyridyl 1503 —CH₂CH₂— bond bond 1-indolyl 1504 —CH₂CH₂— bond bond 2-benzothienyl 1505 —CH₂CH₂— bond bond 2-benzofuranyl 1506 —CH₂CH₂— bond bond 1-benzimidazole 1507 —CH₂CH₂— bond bond 2-naphthyl 1508 —CH₂CH₂CH₂— bond bond phenyl 1509 —CH₂CH₂CH₂— bond bond 3,3-diphenyl 1510 —CH₂CH₂CH₂— bond bond 2-F-phenyl 1511 —CH₂CH₂CH₂— bond bond 3-F-phenyl 1512 —CH₂CH₂CH₂— bond bond 4-F-phenyl 1513 —CH₂CH₂CH₂— bond bond 2-Cl-phenyl 1514 —CH₂CH₂CH₂— bond bond 3-Cl-phenyl 1515 —CH₂CH₂CH₂— bond bond 4-Cl-phenyl 1516 —CH₂CH₂CH₂— bond bond 2-Me-phenyl 1517 —CH₂CH₂CH₂— bond bond 3-Me-phenyl 1518 —CH₂CH₂CH₂— bond bond 4-Me-phenyl 1519 —CH₂CH₂CH₂— bond bond 2-MeO-phenyl 1520 —CH₂CH₂CH₂— bond bond 3-MeO-phenyl 1521 —CH₂CH₂CH₂— bond bond 4-MeO-phenyl 1522 —CH₂CH₂CH₂— bond bond 2-MeS-phenyl 1523 —CH₂CH₂CH₂— bond bond 3-MeS-phenyl 1524 —CH₂CH₂CH₂— bond bond 4-MeS-phenyl 1525 —CH₂CH₂CH₂— bond bond 2-F₃C-phenyl 1526 —CH₂CH₂CH₂— bond bond 3-F₃C-phenyl 1527 —CH₂CH₂CH₂— bond bond 4-F₃C-phenyl 1528 —CH₂CH₂CH₂— bond bond 2,3-diF-phenyl 1529 —CH₂CH₂CH₂— bond bond 2,4-diF-phenyl 1530 —CH₂CH₂CH₂— bond bond 2,5-diF-phenyl 1531 —CH₂CH₂CH₂— bond bond 2,6-diF-phenyl 1532 —CH₂CH₂CH₂— bond bond 3,4-diF-phenyl 1533 —CH₂CH₂CH₂— bond bond 3,5-diF-phenyl 1534 —CH₂CH₂CH₂— bond bond 2,3-diCl-phenyl 1535 —CH₂CH₂CH₂— bond bond 2,4-diCl-phenyl 1536 —CH₂CH₂CH₂— bond bond 2,5-diCl-phenyl 1537 —CH₂CH₂CH₂— bond bond 2,6-diCl-phenyl 1538 —CH₂CH₂CH₂— bond bond 3,4-diCl-phenyl 1539 —CH₂CH₂CH₂— bond bond 3,5-diCl-phenyl 1540 —CH₂CH₂CH₂— bond bond 2-Cl-3-F-phenyl 1541 —CH₂CH₂CH₂— bond bond 2-Cl-4-F-phenyl 1542 —CH₂CH₂CH₂— bond bond 2-Cl-5-F-phenyl 1543 —CH₂CH₂CH₂— bond bond 3-Cl-4-F-phenyl 1544 —CH₂CH₂CH₂— bond bond 3-Cl-5-F-phenyl 1545 —CH₂CH₂CH₂— bond bond 4-Cl-2-F-phenyl 1546 —CH₂CH₂CH₂— bond bond 4-Cl-3-F-phenyl 1547 —CH₂CH₂CH₂— bond bond 2,3-diMeO- phenyl 1548 —CH₂CH₂CH₂— bond bond 2,4-diMeO- phenyl 1549 —CH₂CH₂CH₂— bond bond 2,5-diMeO- phenyl 1550 —CH₂CH₂CH₂— bond bond 2,6-diMeO- phenyl 1551 —CH₂CH₂CH₂— bond bond 3,4-diMeO- phenyl 1552 —CH₂CH₂CH₂— bond bond 3,5-diMeO- phenyl 1553 —CH₂CH₂CH₂— bond bond cyclopropyl 1554 —CH₂CH₂CH₂— bond bond cyclobutyl 1555 —CH₂CH₂CH₂— bond bond cyclopentyl 1556 —CH₂CH₂CH₂— bond bond cyclohexyl 1557 —CH₂CH₂CH₂— bond bond 2-furanyl 1558 —CH₂CH₂CH₂— bond bond 2-thienyl 1559 —CH₂CH₂CH₂— bond bond 2-imidazolyl 1560 —CH₂CH₂CH₂— bond bond 2-pyridyl 1561 —CH₂CH₂CH₂— bond bond 3-pyridyl 1562 —CH₂CH₂CH₂— bond bond 4-pyridyl 1563 —CH₂CH₂CH₂— bond bond N-morpholinyl 1564 —CH₂CH₂CH₂— bond bond N-piperidinyl 1565 —CH₂CH₂CH₂— bond bond 3-Me-2-pyridyl 1566 —CH₂CH₂CH₂— bond bond 4-Me-2-pyridyl 1567 —CH₂CH₂CH₂— bond bond 1-indolyl 1568 —CH₂CH₂CH₂— bond bond 2-benzothienyl 1569 —CH₂CH₂CH₂— bond bond 2-benzofuranyl 1570 —CH₂CH₂CH₂— bond bond 1-benzimidazole 1571 —CH₂CH₂CH₂— bond bond 2-naphthyl 1572 —CH₂CH₂— bond —O— phenyl 1573 —CH₂CH₂— bond —O— 3,3- diphenylmethyl 1574 —CH₂CH₂— bond —O— 2-F-phenyl 1575 —CH₂CH₂— bond —O— 3-F-phenyl 1576 —CH₂CH₂— bond —O— 4-F-phenyl 1577 —CH₂CH₂— bond —O— 2-Cl-phenyl 1578 —CH₂CH₂— bond —O— 3-Cl-phenyl 1579 —CH₂CH₂— bond —O— 4-Cl-phenyl 1580 —CH₂CH₂— bond —O— 2-Me-phenyl 1581 —CH₂CH₂— bond —O— 3-Me-phenyl 1582 —CH₂CH₂— bond —O— 4-Me-phenyl 1583 —CH₂CH₂— bond —O— 2-MeO-phenyl 1584 —CH₂CH₂— bond —O— 3-MeO-phenyl 1585 —CH₂CH₂— bond —O— 4-MeO-phenyl 1586 —CH₂CH₂— bond —O— 2-MeS-phenyl 1587 —CH₂CH₂— bond —O— 3-MeS-phenyl 1588 —CH₂CH₂— bond —O— 4-MeS-phenyl 1589 —CH₂CH₂— bond —O— 2-F₃C-phenyl 1590 —CH₂CH₂— bond —O— 3-F₃C-phenyl 1591 —CH₂CH₂— bond —O— 4-F₃C-phenyl 1592 —CH₂CH₂— bond —O— 2,3-diF-phenyl 1593 —CH₂CH₂— bond —O— 2,4-diF-phenyl 1594 —CH₂CH₂— bond —O— 2,5-diF-phenyl 1595 —CH₂CH₂— bond —O— 2,6-diF-phenyl 1596 —CH₂CH₂— bond —O— 3,4-diF-phenyl 1597 —CH₂CH₂— bond —O— 3,5-diF-phenyl 1598 —CH₂CH₂— bond —O— 2,3-diCl-phenyl 1599 —CH₂CH₂— bond —O— 2,4-diCl-phenyl 1600 —CH₂CH₂— bond —O— 2,5-diCl-phenyl 1601 —CH₂CH₂— bond —O— 2,6-diCl-phenyl 1602 —CH₂CH₂— bond —O— 3,4-diCl-phenyl 1603 —CH₂CH₂— bond —O— 3,5-diCl-phenyl 1604 —CH₂CH₂— bond —O— 2-Cl-3-F-phenyl 1605 —CH₂CH₂— bond —O— 2-Cl-4-F-phenyl 1606 —CH₂CH₂— bond —O— 2-Cl-5-F-phenyl 1607 —CH₂CH₂— bond —O— 3-Cl-4-F-phenyl 1608 —CH₂CH₂— bond —O— 3-Cl-5-F-phenyl 1609 —CH₂CH₂— bond —O— 4-Cl-2-F-phenyl 1610 —CH₂CH₂— bond —O— 4-Cl-3-F-phenyl 1611 —CH₂CH₂— bond —O— 2,3-diMeO- phenyl 1612 —CH₂CH₂— bond —O— 2,4-diMeO- phenyl 1613 —CH₂CH₂— bond —O— 2,5-diMeO- phenyl 1614 —CH₂CH₂— bond —O— 2,6-diMeO- phenyl 1615 —CH₂CH₂— bond —O— 3,4-diMeO- phenyl 1616 —CH₂CH₂— bond —O— 3,5-diMeO- phenyl 1617 —CH₂CH₂— bond —O— cyclopropyl 1618 —CH₂CH₂— bond —O— cyclobutyl 1619 —CH₂CH₂— bond —O— cyclopentyl 1620 —CH₂CH₂— bond —O— cyclohexyl 1621 —CH₂CH₂— bond —O— 2-furanyl 1622 —CH₂CH₂— bond —O— 2-thienyl 1623 —CH₂CH₂— bond —O— 2-pyridyl 1624 —CH₂CH₂— bond —O— 3-pyridyl 1625 —CH₂CH₂— bond —O— 4-pyridyl 1626 —CH₂CH₂— bond —O— 3-Me-2-pyridyl 1627 —CH₂CH₂— bond —O— 4-Me-2-pyridyl 1628 —CH₂CH₂— bond —O— 2-benzothienyl 1629 —CH₂CH₂— bond —O— 2-benzofuranyl 1630 —CH₂CH₂— bond —O— 2-naphthyl 1631 —CH₂CH₂CH₂— bond —O— phenyl 1632 —CH₂CH₂CH₂— bond —O— 3,3- diphenylmethyl 1633 —CH₂CH₂CH₂— bond —O— 2-F-phenyl 1634 —CH₂CH₂CH₂— bond —O— 3-F-phenyl 1635 —CH₂CH₂CH₂— bond —O— 4-F-phenyl 1636 —CH₂CH₂CH₂— bond —O— 2-Cl-phenyl 1637 —CH₂CH₂CH₂— bond —O— 3-Cl-phenyl 1638 —CH₂CH₂CH₂— bond —O— 4-Cl-phenyl 1639 —CH₂CH₂CH₂— bond —O— 2-Me-phenyl 1640 —CH₂CH₂CH₂— bond —O— 3-Me-phenyl 1641 —CH₂CH₂CH₂— bond —O— 4-Me-phenyl 1642 —CH₂CH₂CH₂— bond —O— 2-MeO-phenyl 1643 —CH₂CH₂CH₂— bond —O— 3-MeO-phenyl 1644 —CH₂CH₂CH₂— bond —O— 4-MeO-phenyl 1645 —CH₂CH₂CH₂— bond —O— 2-MeS-phenyl 1646 —CH₂CH₂CH₂— bond —O— 3-MeS-phenyl 1647 —CH₂CH₂CH₂— bond —O— 4-MeS-phenyl 1648 —CH₂CH₂CH₂— bond —O— 2-F₃C-phenyl 1649 —CH₂CH₂CH₂— bond —O— 3-F₃C-phenyl 1650 —CH₂CH₂CH₂— bond —O— 4-F₃C-phenyl 1651 —CH₂CH₂CH₂— bond —O— 2,3-diF-phenyl 1652 —CH₂CH₂CH₂— bond —O— 2,4-diF-phenyl 1653 —CH₂CH₂CH₂— bond —O— 2,5-diF-phenyl 1654 —CH₂CH₂CH₂— bond —O— 2,6-diF-phenyl 1655 —CH₂CH₂CH₂— bond —O— 3,4-diF-phenyl 1656 —CH₂CH₂CH₂— bond —O— 3,5-diF-phenyl 1657 —CH₂CH₂CH₂— bond —O— 2,3-diCl-phenyl 1658 —CH₂CH₂CH₂— bond —O— 2,4-diCl-phenyl 1659 —CH₂CH₂CH₂— bond —O— 2,5-diCl-phenyl 1660 —CH₂CH₂CH₂— bond —O— 2,6-diCl-phenyl 1661 —CH₂CH₂CH₂— bond —O— 3,4-diCl-phenyl 1662 —CH₂CH₂CH₂— bond —O— 3,5-diCl-phenyl 1663 —CH₂CH₂CH₂— bond —O— 2-Cl-3-F-phenyl 1664 —CH₂CH₂CH₂— bond —O— 2-Cl-4-F-phenyl 1665 —CH₂CH₂CH₂— bond —O— 2-Cl-5-F-phenyl 1666 —CH₂CH₂CH₂— bond —O— 3-Cl-4-F-phenyl 1667 —CH₂CH₂CH₂— bond —O— 3-Cl-5-F-phenyl 1668 —CH₂CH₂CH₂— bond —O— 4-Cl-2-F-phenyl 1669 —CH₂CH₂CH₂— bond —O— 4-Cl-3-F-phenyl 1670 —CH₂CH₂CH₂— bond —O— 2,3-diMeO- phenyl 1671 —CH₂CH₂CH₂— bond —O— 2,4-diMeO- phenyl 1672 —CH₂CH₂CH₂— bond —O— 2,5-diMeO- phenyl 1673 —CH₂CH₂CH₂— bond —O— 2,6-diMeO- phenyl 1674 —CH₂CH₂CH₂— bond —O— 3,4-diMeO- phenyl 1675 —CH₂CH₂CH₂— bond —O— 3,5-diMeO- phenyl 1676 —CH₂CH₂CH₂— bond —O— cyclopropyl 1677 —CH₂CH₂CH₂— bond —O— cyclobutyl 1678 —CH₂CH₂CH₂— bond —O— cyclopentyl 1679 —CH₂CH₂CH₂— bond —O— cyclohexyl 1680 —CH₂CH₂CH₂— bond —O— 2-furanyl 1681 —CH₂CH₂CH₂— bond —O— 2-thienyl 1682 —CH₂CH₂CH₂— bond —O— 2-pyridyl 1683 —CH₂CH₂CH₂— bond —O— 3-pyridyl 1684 —CH₂CH₂CH₂— bond —O— 4-pyridyl 1685 —CH₂CH₂CH₂— bond —O— 3-Me-2-pyridyl 1686 —CH₂CH₂CH₂— bond —O— 4-Me-2-pyridyl 1687 —CH₂CH₂CH₂— bond —O— 2-benzothienyl 1688 —CH₂CH₂CH₂— bond —O— 2-benzofuranyl 1689 —CH₂CH₂CH₂— bond —O— 2-naphthyl 

1. A process for preparing a compound of Formula (I),

or a stereoisomer, or a pharmaceutically acceptable salt thereof, comprising coupling an aminolactam 42 and succinic acid derivatives 41 using amide bond syntheses methods, including methods commonly used in peptide syntheses, such as HATU, TBTU, BOR, pyBOP, EDC, CDI, DCC, hydroxysuccinimide, mixed carboxylic anhydride, and phenyl ester mediated couplings, as illustrated in Scheme 9 for the synthesis of aminolactam 43,

A is O; R¹, at each occurrence, is independently selected from: H; C₁-C₆ alkyl substituted with 0-3 R^(1a); C₂-C₆ alkenyl substituted with 0-3 R^(1a); C₃-C₁₀ carbocycle substituted with 0-3 R^(1b); aryl substituted with 0-3 R^(1b); and 5 to 10 membered heterocycle substituted with 0-3 R^(1b); R^(1a), at each occurrence, is independently selected from H, C_(l)-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃; C₃-C₁₀ carbocycle substituted with 0-3 R^(1b); aryl substituted with 0-3 R^(1b); and 5 to 6 membered heterocycle substituted with 0-3 R^(1b); R^(1b), at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C_(l)-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R² is independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, phenoxy, benzyloxy, C₃-C₁₀ carbocycle, C₆-C₁₀ aryl and 5 to 10 membered heterocycle; R³ is —(CR⁷R^(7a))_(n)—R⁴, —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—S(═O)—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—C(═O)—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—N(R^(7b))C(═O)—(CR⁷R^(7a))_(m)—R⁴; —(CR⁷R^(7a))_(n)—C(═O)N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—N(R^(7b))S(═O)₂—(CR⁷R^(7a))_(m)-R⁴, or —(CR⁷R^(7a))_(n)—S(═O)₂N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; R⁴ is H, OH, OR^(l4a), C₁-C₆ alkyl substituted with 0-3 R^(4a), C₂-C₆ alkenyl substituted with 0-3 R^(4a), C₂-C⁶ alkynyl substituted with 0-3 R^(4a), C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), aryl substituted with 0-3 R^(4b), or 5 to 10 membered heterocycle substituted with 0-3 R^(4b); R^(4a), at each occurrence, is independently selected from is H, F, Cl Br I, CF₃, C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), aryl substituted with 0-3 R^(4b), or 5 to 10 membered heterocycle substituted with 0-3 R^(4b); R^(4b), at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy; R⁵ is H, OR¹⁴; C₁-C₆ alkyl substituted with 0-3 R^(5b); C₁-C₆ alkoxy substituted with 0-3 R^(5b); C₂-C₆ alkenyl substituted with 0-3 R^(5b); C₂-C₆ alkynyl substituted with 0-3 R^(5b); C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); aryl substituted with 0-3 R^(5c); or 5 to 10 membered heterocycle substituted with 0-3R^(5c); R^(5b), at each occurrence, is independently selected from: H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶; C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); aryl substituted with 0-3 R^(5c); or 5 to 10 membered heterocycle substituted with 0-3 R^(5c); R^(5c), at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy; R⁶ is H; C₁-C₆ alkyl substituted with 0-3 R^(6a); C₃-C₁₀ carbocycle substituted with 0-3 R^(6b); or aryl substituted with 0-3R^(6b); R^(6a), at each occurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CR₃; R^(6b), at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R⁷, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; R^(7a), at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, aryl and C₁-C₄ alkyl; R^(7b) is independently selected from H and C₁-C₄ alkyl; Z is C₁-C₃ alkyl substituted with 1-2 R¹²; aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or 5 to 10 membered heterocycle substituted with 0-3 R^(12b); R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or 5 to 10 membered heterocycle substituted with 0-3 R^(12b); R^(12b), at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy; B is a seven membered lactam, wherein the lactam is saturated, partially saturated or unsaturated; and wherein each additional lactam carbon is substituted with 0-2 R¹¹; and, optionally, the lactam contains a heteroatom selected from —O—, and —N(R¹⁰)—; R¹⁰ is H; R¹¹ at each occurrence, is independently selected from C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═)₂NR¹⁸R¹⁹, CF₃; C₁-C₆ alkyl substituted with 0-1 R^(11a); aryl substituted with 0-3 R^(11b); C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or 5 to 10 membered heterocycle substituted with 0-3 R^(11b); alternatively, two R¹¹ substituents on the same or adjacent carbon atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused radical; R^(11a), at each occurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b); R^(11b), at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CM, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy; R¹⁴, at each occurrence, is independently selected from H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₆ alkoxyalkyl; R^(l4a) is H, phenyl, benzyl, or C₁-C₄ alkyl; R¹⁵, at each occurrence, is independently selected from H, C₁-C₆ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); R¹⁷ is H, aryl, aryl-CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; R¹⁸, at each occurrence, is independently selected from H, C₁-C₆ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); and R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); and R^(l9b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or phenethyl.
 2. The process according to claim 1 for preparing a compound of Formula I or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: R³ is —(CR⁷R^(7a))_(n)—R⁴, —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; n is 0 or 1; m is 0 or 1; R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy; R⁴ is H, OH, C₁-C₄ alkyl substituted with 0-2 R^(4a), C₂-C₄ alkenyl substituted with 0-2 R^(4a), C₂-C₄ alkynyl substituted with 0-1 R^(4a), C₃-C₆ cycloalkyl substituted with 0-3 R^(4b), aryl substituted with 0-3 R^(4b), or 5 to 10 membered heterocycle substituted with 0-3 R^(4b); R^(4a), at each occurrence, is independently selected from is H, F, Cl, CF₃, C₃-C₆ cycloalkyl substituted with 0-3 R^(4b), phenyl substituted with 0-3 R^(4b), or 5 to 6 membered heterocycle substituted with 0-3 R^(4b); R^(4b), at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; R⁵ is H, OR¹⁴; C₁-C₄ alkyl substituted with 0-3 R^(5b); C₂-C⁴ alkenyl substituted with 0-2 R^(5b); or C₂-C₄ alkynyl substituted with 0-2 R^(5b); R^(5a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, or allyl; R^(5b), at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O; C₃-C₆ cycloalkyl substituted with 0-2 R^(5c), phenyl substituted with 0-3 R^(5c); or 5 to 6 membered heterocycle substituted with 0-2 R^(5c); R^(5c), at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; R⁶ is H; R⁷, at each occurrence, is independently selected from H, F, CF₃, methyl, and ethyl; R^(7a), at each occurrence, is independently selected from H, F, CF₃, methyl, and ethyl; R^(7b) is independently selected from H, methyl, and ethyl; Z is C₁-C₂ alkyl substituted with 1-2 R¹²; C₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₆ carbocycle substituted with 0-3 R^(12b); or 5 to 10 membered heterocycle substituted with 0-3 R^(12b); R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₆ carbocycle substituted with 0-3 R^(12b); or 5 to 10 membered heterocycle substituted with 0-3 R^(12b); R^(12b), at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; B is

R₁₁, at each occurrence, is independently selected from C₁-C₄ alkoxy, Cl, F, ═0, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, CF₃; C₁-C₄ alkyl substituted with 0-1 R^(11a); phenyl substituted with 0-3 R^(11b); C₃-C₆ carbocycle substituted with 0-3 R^(11b); or 5 to 6 membered heterocycle substituted with 0-3 R^(11b); R^(11a), at each occurrence, as independently selected from H, C₁-C₄ alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b); R^(11b) at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; R¹⁵ at each occurrence, is independently selected from H, C₁-C₄ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄ alkyl) R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄ alkyl); R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl) methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or ethoxyethyl; R¹⁸, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and R¹⁹, at each occurrence, is independently selected from H, methyl, and ethyl.
 3. A process for preparing a compound of Formula I or a stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein: Ring B is:


4. A process for preparing a compound of Formula I or a stereoisomer thereof, according to claim 3, further comprising: using protecting groups as illustrated in Scheme 10, in which the succinate half-ester 44 is coupled to aminobenzodiazepine 45 to give ester 46, followed by conversion of the ester group to the primary amide 47,

which compound may further treated to produce a pharmaceutically acceptable salt form.
 5. A process for preparing a compound of Formula I, according to claim 2, as shown in Example 42, comprising (2S,3R) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H 1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide,

or a stereoisomer or pharmaceutically acceptable salt form thereof, according to claim 3, the process comprising the steps of: producing 3-Phenoxybenzyl iodide which filtered product upon evaporation formed a light yellow oil; which product was used in next step without purification; ¹H NMR (CDCl₃) 4.4 (s,2H), 6.8-7.4 (m, 9H);

adding triethylamine (0.76 ml, 5.45 mmol) to a solution of benzodiazepine 50 (910 mg, 3.63 mmol), succinate 9 (980 mg, 3.63 mmol), hydroxybenzotriazole (980 mg., 7.25 mmol) and EDC (870 mg, 4.54 mmol) in 100 ml CH₂Cl₂ at 0 degrees C.; washing the reaction mixture with saturated sodium bicarbonate solution, 1.0 N HCl, brine and dried over MgSO₄; evaporating the organic layer and purifying by column chromatography on silica gel with hexane-ethyl acetate (7:3) yielded 610 mg of benzodiazepine 51 as a white solid. M+H=504.37. ¹H NMR (CDCl₃) 0.8-1.0 (m, 6H), 1.0-1.2 (m, 1H), 1.4-1.5 (d, 9H), 1.6-1.9 (m, 2H), 2.2-2.8 (m, 4H), 4.9-5.2 (m, 2H), 5.6 (dd, 1H), 5.6-6.0 (m, 1H), 7.0-7.6 (m, 9H).,

adding NaH (45 mg, 1.12 mmol) to a solution of benzodiazepine 51 (440 mg, 0.875 mmol) in DMF (20 ml) at 0 degrees was added NaH; stirring the mixture at 0 degrees for 1.5 hr; and adding dropwise a solution of 3-phenoxylbenzyl iodide (330 mg, 1.06 mmol) in 10 ml DMF; allowing reaction mixture to warm to room temperature and stirring it overnight; upon completion of the reaction, the mixture was quenched with water, and the solvent was evaporated under high vacuum, which provided a viscous yellow oil; dissolving the product benzodiazepine 52 in ethyl acetate, and washing it with water (2×), brine and then drying it over MgSO₄; subsequently, evaporating the solvent gave 600 mg of benzodiazepine 52 as a yellow oil which was not further purified. M+H=686.3, M+Na=708.3. ¹H NMR (CDCl₃) 0.8-1.0 (m, 6H), 1.0-1.3 (m, 1H), 1.4-1.5 (d, 9H), 1.5-1.9 (2H), 2.2-2.7 (4H), 4.6-4.8 (d,1H), 4.9-5.2 (m, 2H), 5.6-5.9 (m, 3H), 6.6-7.6 (m, 18H); and finally stirring a solution of benzodiazepine 52 in 40 ml of TFA/CH₂Cl₂ (1:1) overnight at room temperature, and evaporating it to dryness; wherein repeated addition of toluene and evaporation provided 560 mg of 53 as a yellow solid; (M−H=629.1)

adding diisopropylethylamine (0.6 ml, 3.44 mmol) solvent to a solution of benzodiazepine 53 and HATU (410 mg, 1.08 mmol) in 30 ml DMF at 0 degrees; bubbling ammonia gas through the solution, and warming the reaction mixture to room temperature and stirring overnight; adding water and evaporating said solvent under high vacuum providing a yellow solid; and purifying on silica gel using CH₂Cl₂: methanol (10:0.5) yielding 256 mg of said Example 42 M+H=629.2 HNMR (CDCl₃) 0.8-1.0 (m, 6H), 1.2-1.4 (m, 1H), 1.6-2.0 (m, 2H), 2.2-2.8(4H), 4.6-4.8 (m, 1H), 5.05.2 (m, 2H), 5.6-5.9 (m, 3H), 6.2-7.8 (m, 18H).
 6. The process for preparing a compound of Formula I according to claim 2 selected from: (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybonzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2- methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H -1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl) -2H-1,4-benzodiazepin-3-yl[-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifloromothylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl) -2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl) -3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyi)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethly)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl) -3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3(4-trifluoromethylphenyl)benzyl) -2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl) -2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl) -3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl) -butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3(4-trifluoromethylphenyl)benzyl) -2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl) -3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl) -2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl) -butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl) -butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl) -butanediamide; and (2R,3S) N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl) -butanediamide; (2R,3S) N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl) -butanediamide; (2R,3S) N1-[1,3-dihydro-1-((4-Fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl) -butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylproply)-3-(propyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S) N1-]1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S) N1[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl) -butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phyenyl) -2H,1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl) -butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl) -butanediamide; (2R,3S) N1[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl) -butanediamide; (2R,3S) N1[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3yl]-2-(2-methylpropyl)-3-(allyl) -butanediamide; (2R,3S) N1[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl) -butanediamide; (2R,3S) N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazpin-3- yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3dihydro-1-(cyclobutylmethyl)-2-oxo-5(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3-S) N1-[1,3-dihydro-1-(cyclopentylethyl)-2oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S) N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.
 7. A process of preparing a Pharmaceutical composition comprising combining a compound made by the process according to claim 6, and a pharmaceutically acceptable carrier. 